THE PATHOGENESIS OF RHEUMATOID SYNOVITIS - A DUALISTIC VIEW

One intriguing feature of rheumatoid synovitis is the marked enrichmen t in T lymphocytes showing several markers of activation opposed to th e negligible levels of T cell-derived cytokines (CKs). In addition, th e T cell activation phenotype appears to be paradoxical. Very early (C D69), late (HLA-DR) and very late (VLA-1) activation markers are simul taneously expressed by synovial T cells, but few bear interleukin-2 re ceptors (IL-2R). In this report, we challenge the hypothesis of ''inco mplete'' T cell activation to explain this phenomenon and provide evid ence that both preferential recruitment of pre-activated T cells and C D69 induction by endothelial cell contact are involved. Although these findings suggest that only the IL-2R(+) T cell fraction may be potent ially activated via an arthritogenic antigen-specific mechanism, it is possible that the entire synovial T cell population may contribute, v ia cell-to-cell contact or CK release, to rheumatoid synovitis chronic ity. In ag with this point of view, enrichment in fully differentiated CD4(+)CD45RB(dim)CD27(-) T cells, which include Th-l and Th-2 lymphoc ytes, has been reported in rheumatoid arthritis (RA) synovium, probabl y due to their enhanced migratory capacity. Despite these observations , activated synovial T cells produce only minimal amounts of CKs. More importantly, they appear to be biased toward a Th-l phenotype, as the y produce mainly interferon (IFN)-gamma but not IL-4. The altered Th-1 /Th-2 ratio may play a major role in RA pathogenesis, given the proinf lammatory and anti-inflammatory properties respectively exerted in the se T cell subsets. However, this may reflect the immunosuppressive act ivity of synoviocyte/monocyte-derived CKs, such as transforming growth factor (TGF)-beta, IL-10 and tumour necrosis factor (TNF)-alpha. Take n together, these findings suggest a scenario in which chronic inflamm ation is sustained by a dynamic interaction among T cells, synoviocyte s and monocytes within RA synovium. As a consequence, lasting clinical improvements in RA might be expected only if we take a dualistic ther apeutic approach to act on both arms of the immune system.