Modulation of immune complex-induced inflammation in vivo by the coordinate expression of activation and inhibitory Fc receptors

Autoantibodies and immune complexes are major pathogenic factors ill autoim mune injury, responsible for initiation of the: inflammatory cascade and it s resulting tissue damage. This activation results from the interaction of immunoglobulin (Ig)G Fc receptors containing an activation motif(ITAM) with immune complexes (ICs) and cytotoxic autoantibodies which initiates and pr opagates an inflammatory response. In vitro, this pathway can be interrupte d by coligation to Fc gamma RIIB, an IgG Fc receptor containing an inhibito ry motif (ITIM). In this report, we describe the in vivo consequences of Fc gamma RII deficiency in the inflammatory response using a mouse model of I C alveolitis. AI subthreshold concentrations of ICs that fail to elicit inf lammatory responses in wild-type mice, Fc gamma RII-deficient mice develope d robust inflammatory responses characterized by increased hemorrhage, edem a, and neutrophil infiltration. Bronchoalveolar fluids from Fc gamma RII-/- stimulated mice contain higher levels of tumor necrosis factor and chemota ctic activity, suggesting that Fc gamma RII deficiency lowers the threshold of IC stimulation of resident cells such as the alveolar macrophage. In co ntrast, complement- and complement receptor-deficient mice develop normal i nflammatory responses to suprathreshold levels of ICs, while FcR gamma(-/-) mice are completely protected from inflammatory injury. An inhibitory role for Fc gamma RII on macrophages is demonstrated by analysis of Fc gamma RI I-/- macrophages which show greater phagocytic and calcium flux responses u pon Fc gamma RIII engagement. These data reveal contrasting roles for the c ellular receptors for IgG on inflammatory cells, providing a regulatory mec hanism for setting thresholds for IC sensitivity based on the ratio of ITIM to ITAM Fc gamma R expression. Exploiting the Fc gamma RII inhibitory path way could thus provide a new therapeutic approach for modulating antibody-t riggered inflammation.