Newswise — Rheumatoid arthritis (RA) is a condition where the immune system mistakenly attacks the joints, leading to their deterioration. Active RA can be managed with anti-rheumatic medications like methotrexate (MTX), which have shown to enhance clinical outcomes for patients. MTX plays a crucial role in minimizing the harmful joint damage and functional limitations commonly associated with RA. While MTX acts as a folic acid antagonist, its exact mechanisms in RA patients remain largely undisclosed.
Previous studies indicate that MTX has an impact on CD4+ T cells, a type of white blood cell that is thought to be involved in the development of RA. Specifically, it is believed to influence the delicate balance between the activation of interleukin-17-producing helper T (Th17) cells and CD4+ regulatory T (Treg) cells, both of which have implications in RA. Researchers speculate that MTX exerts its effects on CD4+ T cells by suppressing T cell activity and promoting the expansion of Treg cells. However, apart from its influence on folate metabolism, the precise mechanisms through which MTX affects CD4+ T cells in RA patients remain unclear.
That's fascinating! It's great to hear about recent advancements in the understanding of MTX's effects on CD4+ T cells. The discovery that MTX targets tumor protein p63 (TP63) in CD4+ T cells adds valuable insights to the field. The research findings, published online on May 22, 2023, in Volume 8 of the JCI Insight journal, were conducted by a team of researchers led by Dr. Akiro Suto, an Associate Professor at the Department of Allergy and Clinical Immunology at the Graduate School of Medicine, Chiba University, and the Institute for Advanced Academic Research at Chiba University. The team also included Dr. Kensuke Suga, Dr. Shigeru Tanaka, and Dr. Hiroshi Nakajima from the Department of Allergy and Clinical Immunology at Chiba University, as well as Dr. Osamu Ohara from the Department of Applied Genomics at the Kazusa DNA Research Institute. This study marks an important contribution to our understanding of MTX's mechanisms of action and its potential implications for the treatment of rheumatoid arthritis.
Dr. Suto explained the team's motivation behind their research, stating, "We were eager to examine the changes in gene expression before and after MTX treatment, as the drug is known to target CD4+ T cells, yet little is currently understood regarding its impact on gene expression in individuals with active RA." This highlights the team's interest in investigating the effects of MTX on gene expression patterns, particularly within the context of RA patients. By exploring these changes, their study aimed to shed light on the underlying mechanisms of MTX's actions and how they relate to the treatment of active rheumatoid arthritis.
The team utilized DNA microarray profiling of CD4+ T cells from RA patients to explore MTX's impact on gene expression. They employed gene knockdown and RNA sequencing (RNA-Seq) to verify gene function. Notably, TAp63, a TP63 isoform, exhibited high expression in human and mouse Th17 cells. Dr. Suto revealed, "MTX-treated patients showed markedly reduced TAp63 mRNA levels in CD4+ T cells. MTX also suppressed TAp63 proteins in human and mouse Th17 cells. In mice, TAp63 suppression improved autoimmune arthritis."
The RNA-Seq data and gene knockdown experiments uncovered an interesting relationship between TAp63 and another gene called FOXP3, which serves as the master regulator of Treg cells. When TAp63 was suppressed in Treg cells, there was a noticeable increase in the expression of the Foxp3 protein. To confirm this interaction, the researchers conducted a reporter assay, which verified that TAp63 bound to the FOXP3 enhancer and repressed its activity. These findings indicate that TAp63 plays a crucial role in modulating the balance between Th17 and Treg cell differentiation. Consequently, inhibiting TAp63 could potentially enhance the suppressive function of Treg cells and restrict the autoimmune nature of RA.
These significant findings unveil a strong mechanism underlying the action of MTX and highlight the preservation of Treg cells in the context of RA. Moreover, they showcase the potential of TAp63 as a promising therapeutic target for the treatment of RA. These discoveries contribute to our understanding of the complex pathogenesis of RA and open up new avenues for developing innovative therapies aimed at modulating TAp63 and enhancing Treg cell function in RA patients.
About Associate Professor Akira Suto
Dr. Akira Suto earned his Ph.D. from Chiba University in 2003 and is an Associate Professor in the Department of Allergy and Clinical Immunology at the Graduate School of Medicine at Chiba University. His research focuses on the mechanisms of T cell differentiation and the development of autoimmune diseases. He has published over 90 peer-reviewed papers since 2000.
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