Rheumatoid Arthritis (RA) is the most common chronic inflammatory arthritis in Singapore. Recent immunologically based therapeutic interventions using highly specific cytokine-targeting approaches have demonstrated promising clinical efficacy.
Dysregulated immune responses within the inflamed synovial membrane likely contribute directly to cartilage and bone erosion. The levels of proinflammatory cytokines exceed those of their anti-inflammatory counterparts. Synovial T cells exhibit oligoclonality and demonstrate enhanced responses to several autoantigens. Cytokines including IL-15 and IL-18 are present in RA synovium, there they promote not only synovial T cell survival and activation, but also macrophage activation and TNFa production either directly or through cognate interactions with T cells.
We observe previously IL-18 can promote erosive collagen-induced arthritis (CIA) in mice, which is histologically indistinguishable from that induced by collagen in complete Freund's adjuvant. These data identify IL-18 as a potential pro-inflammatory cytokine and should therefore be regarded as a potential therapeutic target, in RA synovitis and in other chronic autoimmune diseases. Recently, several candidate autoantigens have been detected in RA patients generating renewed interest in those mechanisms whereby naive T cells can be primed to become autoreactive T cells and in turn promote inflammatory articular disease. Dendritic cells (DCs) are particularly relevant in this context due to their potent antigen-presenting activity and unique ability to activate naive T cells. We have demonstrated for the first time that transfer of collagen-pulsed, mature DCs is sufficient to induce arthritis in DBA/1 mice. Our data indicated two significant roles for TNFa in arthritis, one during DC maturation and a second in activating the vascular endothelium to allow access of reactive T cells into the joint to initiate synovial inflammation.