Fab-arm exchange is a misnomer

There is increasing research activity aimed at understanding the molecular mechanisms underlying the phenomenon of so-called Fab-arm exchange, which has important implications for immunotherapies involving the anti-inflammatory IgG4 antibodies, and might also be relevant to our understanding of the etiology of the newly-described IgG4-related disease.¹ I would like to point out that “Fab”-arm exchange is a misnomer and is misleading. It implies that only the Fab portion of the antibody is being exchanged; in fact, this dynamic process involves also the exchange of the Fc segment. The assumption underlying the coinage of Fab-arm exchange,² I presume, was that the Fc portion of the IgG4 antibodies is identical and therefore, functionally, only the Fab is being exchanged. This assumption, however, ignores the presence of two isoallotypes³ on IgG4—valine309/leucine309 and arginine409/lysine409. Thus, IgG4 molecules in a person heterozygous at these loci would have Fc of distinct genotypes. Interestingly, one of these Fc genotypes has been shown to have a functional impact on “Fab”-arm exchange: the arginine409 allele enables the Fab-arm exchange, while the lysine409 allele abrogates it.⁴ Thus, in view of the fact that this phenomenon is restricted to the antibodies of IgG4 subclass and that genetically distinct Fab and Fc segments of the antibody are being exchanged, I suggest that Fab-arm exchange be changed to IgG4-arm exchange.