THE PROTECTION RECEPTOR FOR IGG CATABOLISM IS THE BETA(2)-MICROGLOBULIN-CONTAINING NEONATAL INTESTINAL TRANSPORT RECEPTOR

More than 30 years ago, Brambell published the hypothesis bearing his name [Brambell, F. W. R., Hemmings, W. A. & Morris, I. G. (1964) Natur e (London) 203, 1352-1355] that remains as the cornerstone for thinkin g on IgG catabolism. To explain the long survival of IgG relative to o ther plasma proteins and its pattern of increased fractional catabolis m with high concentrations of IgG, Brambell postulated specific IgG '' protection receptors'' (FcRp) that would bind IgG in pinocytic vacuole s and redirect its transport to the circulation; when the FcRp was sat urated, the excess unbound IgG then would pass to unrestricted lysosom al catabolism. Brambell subsequently postulated the neonatal gut trans port receptor (FcRn) and showed its similar saturable character. FcRn was recently cloned but FcRp has not been identified. Using a genetic knockout that disrupts the FcRn and intestinal IgG transport, we show that this lesion also disrupts the IgG protection receptor, supporting the identity of these two receptors. IgG catabolism was 10-fold faste r and IgG levels were correspondingly lower in mutant than in wild-typ e mice, whereas IgA was the same between groups, demonstrating the spe cific effects on the IgG system. Disruption of the FcRp in the mutant mice was also shown to abrogate the classical pattern of decreased IgG survival with higher IgG concentration. Finally, studies in normal mi ce with monomeric antigen-antibody complexes showed differential catab olism in which antigen dissociates in the endosome and passes to the l ysosome, whereas the associated antibody is returned to circulation; i n mutant mice, differential catabolism was lost and the whole complex cleared at the same accelerated rate as albumin, showing the central r ole of the FcRp to the differential catabolism mechanism. Thus, the sa me receptor protein that mediates the function of the FcRn transiently in the neonate is shown to have its functionally dominant expression as the FcRp throughout life, resolving a longstanding mystery of the i dentity of the receptor for the protection of IgG. This result also id entifies an important new member of the class of recycling surface rec eptors and enables the design of protein adaptations to exploit this m echanism to improve survivals of other therapeutic proteins in vivo.