The role of T-cells and their actions in rheumatoid arthritis (RA) has been the focus of a great deal of research for some time [1], mainly as a result of many observations in human patients and experimental animal models. The association of Human Leukocyte Antigen (HLA) DR, a MHC class II cell surface receptor, in RA provides the strongest evidence that CD4+ T-cells are involved in the development of disease [2, 3, 6]. Many other types of T-cells, including CD8+, regulatory T-cells and γδ T-cells have been shown to play different roles in the progression of RA [1, 2, 3, 8]. The mechanisms of disease involved in RA are still unknown; however the main hypothesis theorizes that auto antigens are presented to auto reactive T helper cells, which then orchestrate the inflammatory processes which are characteristic of the disease [3]. The nature of the antigens involved is unknown however several candidates have been suggested, most recently, citrullinated proteins [5, 6].
Work in animal models of arthritis has provided valuable information on the role of T-cells in this complex disease [9]. The importance of T-cells can be shown in the transfer of CD4+ T-cells from an arthritic animal to a healthy animal, which leads to induction of tissue damage in the recipient [2]. Interestingly, recent research has delivered surprising results on the location of T-cells in models of arthritis [4]. In the model of proteoglycan induced arthritis (PGIA), fluorescence-labelled donor T-cells were tracked in SCID mice and the majority were found in the lymph nodes with unexpectedly few found in the joint [5]. In addition, this study also demonstrated that inhibition of T-cell movement from the lymph tissue, using the drug FTY720, did not prevent development or reduce severity of disease in the PGIA model, suggesting that T-cells do not have to be present in the joint for the induction of arthritis in this model [5].
In another study, this time using humanized DR-4 transgenic mice in the collagen induced arthritis (CIA) model, pro-inflammatory T-cells were tracked using a tetramer and were found in the blood and joints during early stages of the disease [3]. However, as disease progressed, the T-cells became undetectable in the joint, rare in the blood and decreased in the lymph tissues. The authors of this study conclude that there may be a “threshold” of activated T-cells circulating that is required for the onset of disease, and once reached the number of active T-cells decreases in the blood, lymph nodes and synovial fluid [3]. These findings raise interesting questions on the link between the location and role of T-cells in models of arthritis.
With all of the evidence for the involvement of T-cells in the development of RA, there is potential for T-cell specific therapies to be the next line in defense against the disease [2]. The most recent T-cell targeted therapy is Abatacept (Orencia®), a fusion protein of the extracellular portion of CTLA4 and human IgG1Fc, which interrupts the “second signal” between the CD28 ligand on the T-cell by binding the CD80/86 ligand on the antigen presenting cell [6, 7, 10]. Clinical trials have shown that Abatacept improves swollen and tender joint complaints and radiological results in patients with disease reduction comarable to some present anti-TNF agents while providing a better safety profile than those drugs [7, 10]. The impressive clinical data for this drug suggests that T-cell specific therapies are promising new agents in the treatment of RA.
The importance of T-cells in RA has been highlighted through a focus of research on the subject, however many questions still remain over their exact function in the pathogenesis of disease. The questions surrounding the location of T-cells during disease, the still unidentified auto antigens that cause the disease and the failure of T-cells to function properly are all areas that demand further research to advance our knowledge of the most common inflammatory condition in humans.
References:
- Fournier, C. (2005). Joint Bone Spine, 72: 527-532
- Skapenko, A. et al (2005). Arthritis Research & Therapy, 7(Suppl 2): S4-S14
- Svendsen, P. et al (2004). The Journal of Immunology, 173: 7037-7045
- Kamradt T, Frey O. (2010). Arthritis Research & Therapy, 12:122
- Angyal, A. et al (2010). Arthritis Research & Therapy, 12:R44
- Andersson, A. et al (2008). Arthritis Research & Therapy 10:204
- Solomon, GE (2010). Bulletin of the NYU Hospital for Joint Diseases, 68(3):162
- Roark, CL. et al (2007). The Journal of Immunology, 179: 5576-5583
- Goronzy JJ, Weyland, CM (2009). Arthritis Research & Therapy, 11:249
- Van Vollenhoven, R.F. (2009) Nature Reviews Rheumatology, 5: 531-541
