Models of T cell invovement in rheumatoid arthritis (RA). (a) The 'classical' model. T cells within the joint recognize fragments of autoantigens presented by local dendritic cells (DCs). As a consequence they produce inflammatory cytokines that directly affect chondrocytes, but mainly prime monocytes and synoviocytes (either fibroblastic or macrophage-like) to produce more substantial amounts of monokines (eg tumor necrosis factor), proteases or glycosidases to effect cartilage destruction and bone remodeling. In this view, there may be local activation of B cells to produce immunoglobulins directed against joint-specific structures, but this is an ancillary pathway. (b) In this model, T-cell activation occurs outside the joint, and is not necessarily caused by joint-specific peptides. The relevant mode of antigen presentation is by B cells, which have picked up rare antigen molecules via their surface immunoglobulin, and are thus preferentially helped. The arthritogenic immunoglobulin they produce (in isolation or in complexed form) then diffuses to the joint. In this locale, immunoglobulin binding or activation by immune complexes provokes the release of chemokines, attracting and priming monocytes to elicit cartilage and joint destruction (and secondary release of B and T cells).