Pathogenesis of RA. The classical clinical feature of rheumatoid arthritis is synovitis. This is a term for swelling of the synovial membrane within joints. Synovitis is both initiated and maintained by a complex interplay between dendritic cells (DCs), T-Cells, B-Cells, macrophages, fibroblasts and osteoclasts15. The leukocyte infiltration of the synovial compartment is primarily due to migration of cells into the area as opposed to local proliferation. Cellular and Mollecular Pathways in RA The strong link between autoantibodies and the development of RA help to highlight the key role that the adaptive immune system plays in the pathogenesis of the disease. The synovium in rheumatoid arthritis contains many myeloid cells and plasmacytoid dendritic cells that express cytokines, HLA class II molecules, and costimulatory molecules that are necessary for T-cell activation and antigen presentation16. The efficacy of abatacept, a drug that blocks T-Cell co-stimulation, provides further evidence for the role of T-Cells in RA. T-cells against citrullinated self-peptides have been identified in individuals with RA. Type 1 (Th1) and Type 17 (Th17) t-helper cells can be activated either in the lymph nodes or in the joint by antigen presenting cells that present autoantigen peptides. These t-cells then activate macrophages and fibroblasts by the secretion of pro-inflammatory mediators including tumour necrosis factor alpha (TNFα), Interleukin 17 (IL-17), Interferon gamma (IFN-γ) and receptor activator of nuclear factor KB ligand (RANK-L)15. Activated macrophages subsequently secrete pro-inflammatory TNF-α, Interleukin 1 beta (IL- 1β), and interleukin 6 (IL-6) which promote the establishment and maintenance of an inflammatory milieu in the synovium15. Activated T cells provide help to autoreactive B cells resulting in the production of anti-ccp and RF autoantibodies. These autoantibodies drive inflammation either by direct macrophage activation or triggering the complement cascade. RANK-L produced by the activated fibroblasts promotes the differentiation of osteoclasts from macrophages15. The pathology is summarised in Figure 2 below.
