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 autoimmune injury, responsible for initiation of the: inflammatory cascade and its 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 propagates an inflammatory response. In vitro, this pathway can be interrupted by coligation to Fc gamma RIIB, an IgG Fc receptor containing an inhibitory 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 IC alveolitis. AI subthreshold concentrations of ICs that fail to elicit inflammatory responses in wild-type mice, Fc gamma RII-deficient mice developed robust inflammatory responses characterized by increased hemorrhage, edema, and neutrophil infiltration. Bronchoalveolar fluids from Fc gamma RII-/- stimulated mice contain higher levels of tumor necrosis factor and chemotactic activity, suggesting that Fc gamma RII deficiency lowers the threshold of IC stimulation of resident cells such as the alveolar macrophage. In contrast, complement- and complement receptor-deficient mice develop normal inflammatory 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 RII-/- macrophages which show greater phagocytic and calcium flux responses upon Fc gamma RIII engagement. These data reveal contrasting roles for the cellular receptors for IgG on inflammatory cells, providing a regulatory mechanism for setting thresholds for IC sensitivity based on the ratio of ITIM to ITAM Fc gamma R expression. Exploiting the Fc gamma RII inhibitory pathway could thus provide a new therapeutic approach for modulating antibody-triggered inflammation.