Kinetics of FcRn-mediated recycling of IgG and albumin in human: Pathophysiology and therapeutic implications using a simplified mechanism-based model

Abstract

The nonclassical MHC class-I molecule, FcRn, salvages both IgG and albumin from degradation. Here we introduce a mechanism-based kinetic model for human to quantify FcRn-mediated recycling of both ligands based on saturable kinetics and data from the literature using easily measurable plasma concentrations rather than unmeasurable endosomal concentrations. The FcRn-mediated fractional recycling rates of IgG and albumin were 142% and 44% of their fractional catabolic rates, respectively. Clearly, FcRn-mediated recycling is a major contributor to the high endogenous concentrations of these two important plasma proteins. While familial hypercatabolic hypoproteinemia is caused by complete FcRn deficiency, the hypercatabolic IgG deficiency of myotonic dystrophy could be explained, based on the kinetic analyses, by a normal number of FcRn with lowered affinity for IgG but normal affinity for albumin. A simulation study demonstrates that the plasma concentrations of IgG and albumin could be dynamically controlled by both FcRn-related and -unrelated parameters.

Introduction

IgG and albumin, despite their disparate forms and functions, have long been known to share two unique characteristics; namely, their lengthy lifespans and an inverse relationship between their serum concentrations and half-lives [1], [2]. These unique characteristics had been explained by a saturable receptor-mediated mechanism that protects both IgG [3] and albumin [4] from intracellular degradation after nonspecific pinocytic uptake, allowing them to be recycled to the cell surface and into the extracellular milieu for continuing circulation. In the last decade the responsible receptor was identified as FcRn, a nonclassical MHC class-I molecule, that bears distinct and independent binding sites for both ligands [5], [6], [7], [8], [9], [10]. FcRn is also largely responsible for the peripartum transport of IgG from mother to offspring [11]. It is further known that animals deficient in FcRn catabolize IgG and albumin more rapidly than the normal animal and manifest low plasma concentrations of both molecules [5], [6], [7], [8], [9], [10], [12], [13].

To characterize the in vivo biological and physiological action of FcRn, several approaches focused exclusively on IgG as the ligand even before FcRn was discovered: the maximum recycling rate (J_max) and the fractional intrinsic plasma catabolic rate (k_int) of IgG were calculated using a receptor-based kinetic model [2], but the IgG concentration at which the half-maximal recycling rate is reached (K_m), a key parameter characterizing FcRn saturation, was not determined. As well, the biological implications of these receptor-mediated processes were not fully evaluated. Although mathematical equations have precisely described the relationship between serum IgG concentration and the fractional plasma catabolic rate (k_cat) in both humans and mice based on sigmoidal curve fitting [14], these predictive equations were empirical rather than mechanistic, and the equation-based parameters lacked physiologically meaningful information such as recycling efficiency and capacity for IgG. Although a mechanism-based IgG pharmacokinetic–pharmacodynamic model has been developed [12], the premise of “kinetic indistinguishability” between plasma and site of catabolism [15] was not considered. Furthermore, there has been no quantitative in vivo characterization of the turnover of albumin, the other FcRn ligand [8], despite its importance in fluid physiology [13].

Two distinct diseases may be manifestations in part of FcRn malfunction. First, familial hypercatabolic hypoproteinemia (FHH) [2], [16], showing hypercatabolism and low plasma concentrations of both IgG and albumin, results from a deficiency of FcRn due to a mutant β2-microglobulin (B2m) gene [10], [17]. Second, patients with myotonic dystrophy (DM) show hypercatabolism and plasma deficiency of only IgG but not albumin. One could explain DM by postulating a mechanism that partially disrupts FcRn-IgG binding, leaving the albumin interaction intact [16], [18], [19]. While these diseases have been extensively investigated, the precise mechanisms of IgG and albumin turnover in these situations have not been fully described.

Although the FcRn-mediated recycling of two ligands is mechanistically and quantitatively well characterized in the mouse [5], it has not been clearly described in human. Therefore, we pursue four objectives in the present study: first, we introduce a mechanism-based FcRn-mediated kinetic turnover model to characterize homeostasis of IgG and albumin. Second, we quantify FcRn-mediated recycling of IgG and albumin in human based on receptor-saturable kinetics using data from the literature. Third, based on our quantitative understanding of FcRn recycling kinetics we offer a hypothesis to explain the hypercatabolic IgG deficiency of DM. Lastly, we simulate steady-state plasma concentrations of IgG and albumin under different physiological conditions to derive implications and potential applications of our model.