The role of TNF-α in rheumatoid arthritis: a focus on regulatory T cells

Abstract

The autoimmune disorder rheumatoid arthritis (RA) causes chronic inflammation and destruction of joints. T cells are a predominant component of the synovial environment in RA, however the functional role of these cells is not yet fully understood. This is in part due to the fact that the balance and importance of the relation of T_regs with T-effector cells in RA is still under investigation. The current treatment regimen for this debilitating disease focuses on controlling symptoms and preventing further joint damage through the use of therapies which affect different areas of the immune system at the synovium. One of the main therapies involves Tumor Necrosis Factor alpha (TNF-α) inhibitors. In the RA immune-environment, TNF-α has been shown to have an influential and extensive but as yet poorly understood effect on T_reg function in vivo, and undoubtably an important role in the treatment of RA. Interestingly, the high levels of TNF-α found in RA patients appear to interfere with the mechanisms controlling the suppressive function of T_regs. Relevance for patients: This review focuses on the conflicting literature available regarding the role played by T_regs in RA and the impact of TNF-α and anti-TNF-α therapies on T_regs in this scenario. Individuals suffering from RA can benefit from better insight of the treatment mechanisms of the immunologic processes which occur throughout this disease, as current treatments for RA focus on several different areas of the immune system at the synovial compartment.

Keywords: TNF-α therapy; joint inflammation; regulatory T cells; rheumatoid arthritis.

Figure 1.. Summary of therapies for rheumatoid arthritis. Treatment regimens for RA have been generally divided into two. The first category contains the non-steroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids, which block effector T-cell activation and reduce inflammation. Other therapies such as immunosuppressants, steroids and biological therapies are grouped under the non-specific term of disease-modifying anti-rheumatic drugs (DMARDs) and these include: Tumor Necrosis Factor alpha (TNF-α) inhibitors (which diretly block TNF-α), Interleukin (IL-1 and IL-6) inhibitors (which target cartilage destruction via synovial fibroblast modulation), immune-suppressants (which inhibit surface adhesion molecules), T-cell activation inhibitors (that bind to differentiated T cells, reducing overall T-cell numbers), B-cell depletors (which act specifically by targetting and destroying B-cells) amd Janus kinase (JAK) inhibitors (blocking signal transduction of cytokine receptors).

Figure 2.. The role of TNF-α in rheumatoid arthritis. Immune regulation is at the heart of RA with the generating of an autoimmune response, with TNF-α being a major player. Dendritic cells, T cells, and B-cells are costimulated, and this leads to T-cell activation and functional differentiation. The stimulated macrophages in turn activate nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB)-dependent signaling, which induces pro-inflammatory cytokines that enhance local inflammation of the synovial membrane (synovitis) and result in damage to cartilage and bones.

Figure 3.. The biochemistry of rheumatoid arthritis focusing On T_regs. In RA patients high levels of TNF-α counteract the suppressive activity of human T_regs, acting as a factor towards defective T_reg function. One mechanism is through increased protein phosphatase 1 (PP1) expression, which physically interacts with the DNA-binding domain of the FoxP3 transcription factor and dephosphorylates Ser418, leading to decreased DNA-binding activity. A second mechanism is through increased protein kinase C-9 (PKC-9) recruitment to the T_reg immunological synapse. Yet another mechanism is via reduced recruitment of disc large homolog 1 (Dlghl) to the immunological synapse. Either or all of these can act in RA patients to reduce T_reg suppressive function.