ROLE OF CD30/CD30L POSITIVE T CELLS IN THE PATHOGENESIS OF RHEUMATOID ARTHRITIS

CD30 and CD30 ligand (CD30L) are members of TNF-receptor and TNF superfamilies respectively. CD30+ T cells are increased in several diseases and interaction between CD30+ and CD30L+ T cells leads either to cell proliferation or to cell apoptosis. In patients with rheumatoid arthritis (RA), soluble CD30 (sCD30) levels seem to reflect the recruitment of CD30+ T cells into the inflamed joints and are predictive of a positive response to classical and biological immunosuppressive therapy. We have evaluated levels of sCD30 in the sera of RA patients and the presence of soluble CD30L (sCD30L) in the sera and synovial fluid of patients with RA. We found high levels of sCD30L in sera and synovial fluid of RA patients; moreover we correlated high levels of sCD30 and sCD30L with a good or negative response to anti-TNF-α therapy, respectively. We have observed that CD30L is shedded upon direct contact of CD30+/CD30L+ T cells. We then wanted to define whether sCD30L binds surface CD30 molecule and is functionally active. Indeed sCD30L binds surface CD30 constitutively expressed by Jurkat cell line and inhibit cell proliferation by inducing cell apoptosis. Our findings suggest that circulant sCD30L is functionally active and that it may favor persistence of active inflammation by inducing apoptosis of CD30+ T cells, known to downmodulate inflammation since they mainly belongs to the Th2 phenotype. We have also studied the stimulation of CD30L+ T cells obtained from peripheral blood of healthy donors and from RA patients’ sera synovial fluid. Preliminary data from real time PCR, evaluation of cytokines in the supernatant by ELISA and cytokine secretion assay by FACS analysis have suggested involvement of CD30/CD30L signalling in polarization of T cells towards a Th17 phenotype that have proinflammatory features. Moreover we want to mention that in the synovial fluid of patients with RA the number of CD30+ T cells is high and that nearly 50% of Treg cells express CD30, suggesting an attempt to downmodulate the ongoing inflammatory process. Finally we have investigated cytokines release by neutrophils upon CD30/Fc chimera stimulation: we have detected an increase in IL-8 secretion when neutrophils were incubated with both LPS and CD30/Fc chimera while a decrease in MMP-9 in the same stimulus conditions. In conclusion, the results obtained suggest that the complex signalling of CD30 and CD30L+ cells system, also through the intervention of the soluble molecules, is implicated in the pathogenesis and progression of rheumatoid synovitis depending on the pro- or antinflammatory effect that eventually prevails.