The T cell system in rheumatoid arthritis: activated or defective?

Rheumatoid Arthritis (RA) is characterised by the presence of activated lymphocytes in the synovial compartment, which are classically considered to be of particular importance to the pathogenesis of the disease. We have shown that activated lymphocytes are also found in the rheumatoid lymph nodes and peripheral blood, and that their proportions are increased in early or active disease. Double-labelling experiments showed that T cell subsets within the activated circulating lymphocytes resemble closely those found in the synovium, and suggested an important role for circulating activated lymphoid populations in the pathogenesis of RA. In vitro studies indicate that although rheumatoid lymphocytes express activation markers, they are functionally deficient. This is well established in the case of synovial lymphocytes. We have demonstrated that functional defects are also present in circulating rheumatoid lymphocytes, which show a decreased autologous mixed leucocyte response (AMLR), corrected partially by the addition of exogenous IL-2. They also proliferate poorly in response to PHA and produce significantly less IL-2 than normal controls. This is more marked in patients with active or complicated RA. These defects cannot be explained by a lack of CD4+2H4+ cells which we have shown to be the major IL-2-producing circulating lymphocyte subpopulation. These findings suggest an intrinsic-functional rather than a numerical deficiency of the IL-2 producing T cells in RA. In recent experiments we have shown that non-lymphoid populations, such as activated phagocytic cells, are also involved in the deficient rheumatoid T cell function, partly via the production of prostaglandins and reactive oxygen intermediates. We and others have demonstrated that the latter may significantly and selectively affect lymphocyte viability and function. These findings may explain the differences in the functional capacity of lymphocytes frequently observed between cells derived from different sites or at different stages of the disease. We suggest that it is not lymphocyte activation as such, but its defective nature, that is of pathogenetical importance in RA. Furthermore, the T cell system should not be viewed and studied in isolation in this disease, but its interactions with inflammatory cells should be taken into account.