C5a and Fcgamma receptors: a mutual admiration society

Phagocytosis is a key process in protection of the host against pathogens and in provision of antigens for the immune response. Synergism between C3b and IgG and their receptors in promoting adherence to and then ingestion of an antigen has been recognized for decades. Only more recently, however, has cross-talk between another complement activation fragment, the anaphylatoxin C5a, and Fcgamma receptors (FcgammaRs) been defined. In this issue of the JCI, C5a is shown to signal, via its receptor, the upregulation of activating (proinflammatory-type) FcgammaRs. Moreover, engagement of FcgammaRs by the IgG-bearing immune complex instructs the cell to synthesize more C5, from which C5a is derived. Thus, this work establishes a feedback loop whereby FcgammaR expression and function are enhanced, a very desirable event in concert with an infection but potentially deleterious in autoimmunity.