Destructive arthritis in the absence of both FcγRI and FcγRIII

Fe receptors for IgG (Fc gamma R) have been implicated in the development of arthritis. However, the precise contribution of the individual Fc gamma R to joint pathology is unclear. In this study, the role of the different Fc gamma R was assessed both in an active and in a passive mouse model of arthritis by analyzing disease development in double and triple knockout (KO) offspring from crosses of Fc gamma RI KO, Fc-gamma RIII KO, Fc gamma RI/III double KO, or FcR gamma-chain KO with the Fc gamma RII KO on C57BL6 background, which is susceptible for collagen-induced arthritis (CIA). In the active CIA model, onset was significantly delayed in the absence of Fc gamma RIII, whereas incidence and maximum severity were significantly decreased in FeyRI/II/III triple KO but not in Fc gamma RII/III double KO and Fc gamma RI/II double KO mice as compared with Fc gamma RII KO animals. Remarkably, fully destructive CIA developed in Fc gamma RI/II/III triple KO mice. In contrast, FcR gamma/Fc gamma RII double KO mice were resistant to CIA. These findings were confirmed with the passive KRN serum-induced arthritis model. These results indicate that all activating Fc gamma R play a role in the development of arthritis, mainly in the downstream effector phase. Fc-gamma RIII is critically required for early arthritis onset, and Fc gamma RI can substantially contribute to arthritis pathology. Importantly, Fc gamma RI and Fc gamma RIII were together dispensable for the development of destructive arthritis but the FcR gamma-chain was not, suggesting a role for another FcR gamma-chain associated receptor, most likely Fc gamma RIV. In addition, Fc gamma RII plays a negative regulatory role in both the central and effector phase of arthritis.