Fc[gamma]RIV: A Novel FcR with Distinct IgG Subclass Specificity

Mouse IgG subclasses display a hierarchy of in vivo activities, with IgG2a and IgG2b showing the greatest protective and pathogenic properties. These enhanced activities result, in part, from their ability to bind to a novel, γ chain-dependent, activating IgG Fc receptor, FcγRIV. FcγRIV maps in the 75 kb genomic interval between FcγRII and FcγRIII; its expression is restricted to myeloid lineage cells, and it binds to IgG2a and IgG2b with intermediate affinity. No binding to IgG1 or IgG3 was observed. Blocking FcγRIV binding to pathogenic anti-platelet antibodies is sufficient to protect mice from antibody-induced thrombocytopenia. Thus, the FcγR system has evolved distinct activation receptors displaying selectivity for IgG subclasses, with IgG1 antibodies exclusively dependent on FcγRIII, whereas IgG2a and IgG2b show preferential dependence on FcγRIV activation. These distinct binding affinities for the IgG subclasses to FcγRs account for their differential protective and pathogenic activities in vivo.