Methrotexate Treatment Inmunomodulates Abnormal Cytokine Expression by T CD4 Lymphocytes Present in DMARD-Naïve Rheumatoid Arthritis Patients
CD4<sup>+</sup>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 establish...
Main Authors: | , , , , , , , , , , |
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Format: | Article |
Language: | English |
Published: |
MDPI AG
2020-09-01
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Series: | International Journal of Molecular Sciences |
Subjects: | |
Online Access: | https://www.mdpi.com/1422-0067/21/18/6847 |
Summary: | CD4<sup>+</sup>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 (T<sub>N</sub>), central (T<sub>CM</sub>), effector memory (T<sub>EM</sub>) and effector (T<sub>E</sub>) CD4<sup>+</sup> 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<sup>+</sup>T-lymphocyte subsets and cytokine expression were measured using flow cytometry. New-onset DMARD-naïve RA patients showed a significant expansion of IL-17A<sup>+</sup>, IFNγ<sup>+</sup> and IL-17A<sup>+</sup>IFNγ<sup>+</sup> CD4<sup>+</sup>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 T<sub>N</sub> and T<sub>MC</sub> CD4<sup>+</sup>T-lymphocytes and IFNγ producing T<sub>N</sub>, T<sub>CM</sub>, T<sub>EM</sub> CD4<sup>+</sup>T-lymphocytes with respect to responders. After 6 months, the numbers of CD4<sup>+</sup>IL-17A<sup>+</sup>T<sub>N</sub> remained significantly increased in nonresponders. In conclusion, CD4<sup>+</sup>T-lymphocytes in new-onset DMARD-naïve RA patients show IL-17A and IFNγ abnormalities in T<sub>N</sub>, indicating their relevant role in early disease pathogenesis. Different patterns of CD4<sup>+</sup> modulation are identified in MTX responders and nonresponders. |
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ISSN: | 1661-6596 1422-0067 |