Fc gamma Receptors and severe cartilage destruction in experimental arthritis.

Contains fulltext : 26925.pdf (publisher's version ) (Open Access)Rheumatoid arthritis (RA) is a chronic inflammatory joint disease, which is characterized by uncontrolled proliferation of synoviocytes and massive infiltration of leucocytes. The perpetuation of synovitis often results in erosion of cartilage and bone. Although RA is considered as an autoimmune disease, the auto-antigen is still unknown. It is thought however, that immune complexes (IC) play a dominant role in the pathogenesis of RA by activation of macrophages via binding to Fc receptors (Fc Rs). In this thesis, the role of the individual Fc Rs in joint inflammation and cartilage destruction was investigated. Fc RI and III are both activating receptors and it was demonstrated that in experimental IC-mediated arthritis models, Fc RIII is the most important receptor regulating joint inflammation. Fc RI is crucial in the development of cartilage damage and this role is even more pronounced in T cell dependent IC-mediated arthritis. Interferon (IFN)- is a cytokine mainly produced by T cells and IFN- is able to increase expression of Fc RI. The latter might result in a more pronounced role in cartilage damage for this receptor. To investigate this, IFN- was overexpressed in a passive IC-arthritis. This experiment showed that cartilage damage became more severe, and it was found that chondrocyte death was specifically mediated by Fc RI. Activation via Fc RI results in oxygen radical production by macrophages and this might result in aggravation of cartilage damage. We investigated the role of oxygen radicals in the development of cartilage damage and we demonstrated that chondrocyte death is induced by oxygen radicals, whereas enzyme-mediated cartilage matrix destruction is partly regulated by oxygen radical production. In this thesis we clearly demonstrate that Fc Rs are important in the development of cartilage damage in experimental arthritis models. A specific role for Fc RI in the induction of chondrocyte death was found, which might be the result of oxygen radical production after binding of ICs.RU Radboud Universiteit Nijmegen, 20 mei 2005Promotor : Berg, W.B. van den Co-promotores : Lent, P.L.E.M. van, Verbeek, J.S.176 p