Methrotexate Treatment Inmunomodulates Abnormal Cytokine Expression by T CD4 Lymphocytes Present in DMARD-Naive Rheumatoid Arthritis Patients

• Type of Material: Article
• Authors: Jorge Monserrat Sanz, University of Alcalá; Cristina Bohorquez, University of Alcalá; Ana Maria Gomez, University of Alcalá; Atusa Movasat, University of Alcalá; Ana Perez, Instituto Ramón y Cajal de Investigación Sanitaria; Lucia Ruiz, University of Alcalá; David Diaz, University of Alcalá; Ana Isabel Sanchez, University of Alcalá; Fernando Albarran, University of Alcalá; Ignacio Sanz, Emory University; Melchor Alvarez-Mon, University of Alcalá
• Language: English
• Date: 2020-09-01
• Publisher: MDPI
• Publication Version: Final Published Version
• Copyright Statement: © 2020 by the authors.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3390/ijms21186847
• Title of Journal or Parent Work: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
• Volume: 21
• Issue: 18
• Start Page: 1
• End Page: 17
• Grant/Funding Information: This work was partially supported by grants from the Fondo de Investigación de la Seguridad Social, Instituto de Salud Carlos III (PI18/01726), Spain and the Programa de Actividades de I+D de la Comunidad de Madrid en Biomedicina (MITIC-CM, S2017/BMD-3804), Madrid, Spain.
• Keywords: methotrexate response; naive rheumatoid arthritis; CD4+T-lymphocytes; Physical Sciences; SYNOVIAL-FLUID; STAT expression; DIFFERENTIATION; CLASSIFICATION; Chemistry; PATHOGENESIS; Chemistry, Multidisciplinary; PERIPHERAL-BLOOD; METHOTREXATE; AMERICAN-COLLEGE; EFFECTOR; Life Sciences & Biomedicine; CELL SUBSETS; IFN gamma; Science & Technology; MEMORY; IL-17A; Biochemistry & Molecular Biology
• Research Categories: Biology, Molecular; Health Sciences, Pathology; Chemistry, Biochemistry

Abstract

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-naïve RA patients, we investigated the pattern of IFNγ, IL-4 and IL-17A expression by naïve (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 IFNγ, 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-naïve RA patients showed a significant expansion of IL-17A+, IFNγ+ and IL-17A+IFNγ+ 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 IFNγ 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-naïve RA patients show IL-17A and IFNγ abnormalities in TN, indicating their relevant role in early disease pathogenesis. Different patterns of CD4+ modulation are identified in MTX responders and nonresponders.