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 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 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 principal agents provocateurs in 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 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).
The T cell perturbation in these models was proposed to correspond to responses to joint-specific antigens, which could occur for one of several reasons: aberrant selection of an autoimmune repertoire in the thymus; unmasking of cryptic self-epitopes or epitope spreading after a local response to a microbe; or molecular mimicry after a distant infection. In some variants, it was proposed that primary alterations in joint antigen-presenting cells led to presentation of neo-antigens to T cells [10]. The following were the arguments proposed in support of such models:
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(1)
The linkage that was discovered between RA and particular major histocompatibility complex (MHC) class II haplotypes [11], with sequence motifs shared between DRβ alleles linked to susceptibility [12]. As the main function of MHC class II molecules is to present peptides to T cells, this implied a determining role for the presentation of particular peptides.
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(2)
The importance of T cells in animal models of RA, such as collagen-induced arthritis (CIA), T-cell populations or clones being able to provoke disease in normal mice.
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(3)
The presence of T lymphocytes in synovial tissue and fluid.
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(4)
The activated/memory phenotype of these T cells, suggesting that they are involved in a local immune response [6].
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(5)
Reports of oligoclonal expansion of these infiltrating T cells [13,14], implying reactivity to a restricted set of antigenic peptides or to a superantigen.
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(6)
The beneficial effect of therapies that target T cells, such as treatment with anti-CD4 monoclonal antibodies [15].
This 'T-cell centric' paradigm was conceptually similar to the favored interpretations of other T-cell-mediated autoimmune diseases, such as type I (insulin dependent) diabetes mellitus, in which autoantigen recognition by T cells appears to be the primary trigger of tissue destruction. It led to proposals of therapeutic strategies designed to block T-cell receptors (TCRs) that are reactive to joint antigens [16]. Issues remaining at the forefront were to identify the joint-specific T cell antigens in order to pinpoint the TCR V regions used in their recognition, why these autoantigens are uniquely recognized in diseased individuals, and to understand the adhesive interactions that concentrate T cells in the joint.