The Role of Fc Gamma Receptors in Experimental Arthritis

University dissertation from Uppsala : Acta Universitatis Upsaliensis

Abstract: Induction of collagen-induced arthritis (CIA), an animal model for human rheumatoid arthritis, is dependent on anti-collagen type II (CII) antibodies. The effector mechanism by which autoantibodies contribute to inflammatory reactions in autoimmune diseases is not well understood. In this thesis I have studied the effector pathways used by IgG anti-CII antibodies to initiate arthritis, namely the IgG Fc receptors (Fc?Rs) and the complement system. We have found that Fc?RIII is crucial for development of CIA, as CII-immunized mice lacking this receptor do not develop arthritis and IgG1 and IgG2b anti-CII antibodies require Fc?RIII to trigger arthritis when transferred to naïve mice. The antibody-mediated arthritis was further enhanced in mice deficient in the inhibitory Fc?RIIB, indicating that Fc?RIIB regulates the activation of Fc?RIII. Furthermore, we demonstrate that Fc?RIII exist as three distinct haplotypes in mice, Fc?RIII:H, Fc?RIII:V and Fc?RIII:T. Mice expressing the Fc?RIII:H haplotype are more susceptible to CIA than mice expressing the Fc?RIII:V haplotype, indicating that certain Fc?RIII haplotype predisposes for CIA. We also show that the most likely Fc?RIII-expressing effector cell in CIA is the macrophage, since Fc?RIII-expressing macrophages exclusively can induce arthritis in Fc?RIII-deficient mice challenged for CIA.The complement system was also investigated in development of CIA. We found that this effector pathway is also necessary for onset of arthritis, as CIA was inhibited by treatment with anti-complement factor 5 (C5) antibodies. C5-deficient mice could neither develop CIA unless provided with C5-containing sera. Taken together, the work presented in this thesis indicates that Fc?Rs and the complement system are crucial for the induction of experimental arthritis. These findings are important for understanding the mechanisms behind rheumatoid arthritis and blocking of these effector pathways may in the future be used as treatment of rheumatoid arthritis.