Certainly, there is a burden of proof to identify pathogenic antibodies in serum from RA patients, and to test whether any of the known autoreactivities in RA patients [25] might have a pathogenic role similar to that of anti-GPI in mice

Certainly, there is a burden of proof to identify pathogenic antibodies in serum from RA patients, and to test whether any of the known autoreactivities in RA patients [25] might have a pathogenic role similar to that of anti-GPI in mice. histocompatibility complex, T lymphocyte, transgenic == Introduction == Favoured explanations for the pathogenesis of RA have changed several times over the past four decades, and our understanding of this mysterious disease remains nebulous. Today, few dispute that the effector phase involves angiogenesis, chemotaxis and activation of monocytic cells, anarchic proliferation of synoviocytes, and the release of a witch’s brew of inflammatory cytokines, proteases and glycolytic enzymes, which ultimately results in cartilage and bone destruction. The tantalizing unanswered questions relate to the upstream steps that initiate this process; we have many clues, but little definitive TMUB2 information. == Development of autoimmune paradigms in rheumatoid arthritis == The role of immunological perturbations in starting the arthritis process seems reasonably established, but there have been several changes in the reigning paradigm to explain how autoimmune deviation provokes inflammation and destruction of the joint. In the 1960s, a series of immunochemical findings placed RA in the realm of B lymphocyte disorders, via their immunoglobulin products. These findings include the following: the frequent detection of autoantibodies, in particular of rheumatoid factor (RF; anti-immunoglobulin G); the presence of immune complexes and of reduced complement levels in the joint; and the observation of immunoglobulin deposits and of intracytoplasmic inclusions, composed of immunoglobulins and complement, in phagocytes. These findings suggested a paradigm according to which local immune responses, taking PF-04979064 place in the joint and directed against joint components, produce arthritogenic autoantibodies [1]. These immunoglobulins would then complex with their specific antigen, activating resident phagocytic cells of the synovial lining, and starting the complement cascade. Soluble mediators produced as a result would attract more monocytic cells and PF-04979064 stimulate anarchic proliferation of synoviocytes. The presence in RA synovium of plasma cells and B lymphocytes organized in follicle-like formations gave a cellular footing to this idea. Some investigators (eg Ohno and Cooke [2]) argued for a related paradigm by which a microbe-initiated systemic B-cell response resulted in an immune complex disease. During the ensuing 20 years, however, these notions changed, with B cells losing precedence to T cells as the principalagents provocateursin RA. The relevance of RF to RA pathogenesis became rather suspect, because RF is absent in a substantial proportion of RA patients and, conversely, high-affinity somatically mutated RF was found in many other instances of chronic immune stimulation [3]. Other autoantibodies were even more inconstant. Furthermore, no evidence for directly pathogenic antibodies in RA patients was obtained [4,5]. Several arguments [6,7,8] gave credence to an alternative paradigm that is centred on T cells; synovitis was no longer thought to be induced by antibodies, but rather by a cell-mediated process akin to delayed-type hypersensitivity, involving the local activation of T cells by antigen-presenting cells. This stimulation PF-04979064 released inflammatory cytokines, which activated synoviocytes and monocytes, initiating the monocyte-mediated destructive process described above. Although there was some debate as to the relative roles of T and inflammatory cells once the disease had started [6,9], these views all postulated that joint autoantigen recognition by T cells, and not by antibodies, was at the root of RA (Fig.1a). == Figure 1. == 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 PF-04979064 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,.