Volume 27, Issue 7, Pages 343-348 (July 2006) Perspective – FcRn transports albumin: relevance to immunology and medicine  Clark L. Anderson, Chaity Chaudhury, Jonghan Kim, C.L. Bronson, Manzoor A. Wani, Sudhasri Mohanty  Trends in Immunology  Volume 27, Issue 7, Pages 343-348 (July 2006) DOI: 10.1016/j.it.2006.05.004 Copyright © 2006 Elsevier Ltd Terms and Conditions

Figure 1 Homeostasis of albumin and IgG in a normal 70kg person. The body pools of albumin (red) and IgG (blue) between the two major fluid compartments of the body, the intravascular (plasma) compartment and the extravascular compartment are shown. Also shown are: total body mass for both proteins; the steady state concentrations, volumes and distribution in the two compartments; the rates of degradation and production; and the rates of exchange between the two compartments. Redrawn from Refs [3], [6] and [47]. Abbreviations: d, day; g, grams; L, liters; vs, versus. Trends in Immunology 2006 27, 343-348DOI: (10.1016/j.it.2006.05.004) Copyright © 2006 Elsevier Ltd Terms and Conditions

Figure 2 Relative fractional catabolic rates versus steady-state plasma concentrations for several plasma proteins. Redrawn from the original in ref. [48], which was compiled from several sources in the literature, cited therein. The data for IgM, IgA, IgD, and IgE are from later sources (see main text). Note also that fractional catabolic rates are expressed relative to normal values, so the shapes of these curves should be considered only approximate. In parentheses in the line labels are the half-lives, in days, for the several proteins. Trends in Immunology 2006 27, 343-348DOI: (10.1016/j.it.2006.05.004) Copyright © 2006 Elsevier Ltd Terms and Conditions

Figure 3 FcRn protects from degradation many more albumin molecules than IgG molecules but, in FcRn-deficient mice, the half-life of albumin is only minimally shortened compared with IgG. The turnover rates for albumin (red) and IgG (blue) are drawn on a semi-quantitative scale for a whole 25g mouse represented as two forking arrows. Shown are the rates of endocytosis (destined for degradation) from the left, the rates of degradation by lysosomes as curved arrows, and the rates recycled or saved from degradation by FcRn to the right. At steady-state, when the rates of production and degradation are equal, the rate of endocytosis, presumably identical between the two strains, is the product of albumin clearance (CL) in the KO strain (in the absence of FcRn-protection from degradation) and the plasma albumin concentration of the WT strain. The FcRn-mediated recycling rate is the product of clearance differences between KO and WT strains and the plasma albumin concentration of the WT. The rate of degradation is the difference between the rates of endocytosis and recycling. Note that although a smaller fraction of moles of albumin [1/2=775/(775+775)] than IgG [4/5=22/(22+6)] is salvaged from degradation, the ratio of albumin moles saved to IgG moles saved is remarkably high, namely (35/1=775/22). Calculations from Kim et al. [19]. Abbreviation: d, day. Trends in Immunology 2006 27, 343-348DOI: (10.1016/j.it.2006.05.004) Copyright © 2006 Elsevier Ltd Terms and Conditions

Figure 4 Representative evidence that albumin is catabolized in the plasma compartment. Following an intravenous dose of radio-iodinated albumin into young adult human males at time zero, plasma (P*) and daily urine (U*) radioactivity were measured over 3 weeks. Total body radioactivity (T*) was calculated as dose minus cumulative U*, with fecal excretion assumed to be 10% of urinary values. Shown are the ratios of U*/T* (green) and U*/P* (orange), expressed as percent of urinary excretion per day (%/day) plotted against time; this is identical to the fractional catabolic rate. Note that U*/P* for albumin is constant over time, suggesting that degradation occurs in a fluid compartment kinetically indistinguishable from the plasma space. Redrawn from Ref. [36]. Trends in Immunology 2006 27, 343-348DOI: (10.1016/j.it.2006.05.004) Copyright © 2006 Elsevier Ltd Terms and Conditions