On the role of complement and Fc gamma-receptors in the Arthus reaction

Abstract

The contribution of either the complement system or the activation of Fc receptors for IgG (FcyRs) to the inflammatory response in immune complex (IC) disease is puzzling. A series of studies has been performed in mice with engineered deficiencies of either FcgammaRs, the complement components C3, C4 or the C5a receptor. In addition, different C5-deficient mice strains have been evaluated. Mice with gene targeted disruption of the gamma-subunit, which mediates surface expression and signal transduction of the high affinity Fc receptor type I for IgG (FcgammaRI), the low affinity receptor Fc receptor type III for IgG (FcgammaRIII) and the high affinity receptor type I for IgE (IgepsilonRI), showed an impaired inflammatory response in the reverse passive Arthus reaction in skin, peritoneum and lung. These data suggest, that the activation of FgammaRs is the initial event triggering the inflammatory cascade in IC disease. On the other hand, C5aR deficient mice are either protected from tissue injury induced by ICs, as in the lung, or the degree of the inflammatory response is markedly attenuated, as in peritoneum and skin. A detailed analysis of data obtained with the different knock-out strains revealed that both the activation of the complement system as well as the activation of different effector cells via FcgammaRs contribute to the inflammatory sequelae leading to tissue destruction in IC disease. The relative contributions of FcgammaRI or FcgammaRIII and the main effector cells through which these receptors mediate their effector functions are tissue dependent. The activation of the C5a receptor pathway appears to be the prominent contribution of the complement system.