TThe Major Histocompatibility Complex–related Fc Receptor for IgG (FcRn) Binds Albumin and Prolongs Its Lifespan

Abstract

Introduction : Albumin is a heart-shaped molecule of 67 kD that constitutes two-thirds of the protein mass of serum. Likened to a tramp steamer, it transports a great assortment of molecules such as fatty acids, bile acids, eicosanoids, vitamins, hormones, ions, toxins, and drugs. As well albumin endows blood with most of its colloid osmotic pressure and is the major pH buffering protein of serum (1).

For nearly a half century it has been known that the fractional catabolic rate of albumin is directly related to its serum concentration (2). Thus, the half-life of infused albumin in analbuminemic patients is as long as 115 d compared with 20 d in the normal individual (3). This same direct relationship of concentration to catabolism is characteristic of IgG, but not of several other serum proteins such as fibrinogen, transferrin, haptoglobin, IgA, and IgM (4, 5). Proposing an explanation for the direct relationship, Brambell presented the now widely held hypothesis that IgG is protected from degradation by an Fc receptor–mediated mechanism (6). Specifically, IgG is pinocytosed along with other serum proteins by many cells of the body and is transported to an acidic intracellular compartment where it encounters FcRn, the MHC-related Fc receptor that binds IgG with high affinity at low pH but shows no affinity at physiologic pH (reference 7; for reviews, see references 8 and 9). FcRn effectively diverts IgG from a degradative fate in lysosomes, instead transporting it back to the cell surface where under the influence of neutral pH it dissociates from the receptor and is free to recycle. The lifespan of IgG is thus prolonged relative to other serum proteins not similarly protected. Despite this progress in understanding IgG catabolism, the mechanism by which albumin half-life is prolonged has not been explored.

In 1966, however, Schultze and Heremans conjectured that a mechanism identical to that proposed by Brambell for protecting IgG from degradation could be applied to albumin as well (5). Such a hypothesis has three testable predictions: that FcRn binds albumin in addition to IgG; that FcRn-deficient mice catabolize albumin more rapidly than normal mice; and that the serum albumin concentration in FcRn-deficient mice is low. We have affirmed all three of these predictions.