Evidence to support the cellular mechanism involved in serum IgG homeostasis in humans

Abstract

IgG is the most abundant serum antibody and is an essential component of the humoral immune response. It is known that the 'neonatal' Fc receptor (FcRn) plays a role in maintaining constant serum IgG levels by acting as a protective receptor which binds and salvages IgG from degradation. However, the cellular mechanism that is involved in serum IgG homeostasis is poorly understood. In the current study we address this issue by analyzing the intracellular fate in human endothelial cells of IgG molecules which bind with different affinities to FcRn. The studies show that IgG which do not bind to FcRn accumulate in the lysosomal pathway, providing a cellular explanation for short serum persistence of such antibodies. We have also investigated the saturability of the homeostatic system and find that it has limited capacity. Our observations have direct relevance to the understanding and treatment of IgG deficiency, and to the effective application of therapeutic antibodies.

Neonatal FcR Expression in Bone Marrow-Derived Cells Functions to Protect Serum IgG from Catabolism

“…This function of FcRn allows the absorption of maternal IgG by the newborn across the small intestine or the placenta. Second, FcRn can bind to internalized IgG in an acidic endosome and recycle it back to the cell surface (13). This function of FcRn protects internalized IgG from catabolism.…”

“…In fact, FcRn has been shown to be highly expressed in a variety of different endothelial beds. A significant body of work has established that FcRn, expressed in endothelial cells, intercepts internalized IgG and returns it to the circulation thus protecting it from lysosomal degradation (13,(15)(16)(17)(18). Although expression of the homeostatic IgG receptor in the vascular endothelium makes logical sense, FcRn is also expressed at other sites in adult animals.…”

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

“…1A) features a functional catabolic and recycling site within the vascular compartment consisting of endosome-rich endothelium [24] into which plasma IgG is constitutively pinocytosed by a fluid-phase endocytic process at a fractional uptake rate (k up ), which is FcRn-independent since FcRn binding takes place after acidic sorting endosomes are formed [25], unlike cell-surface receptor-mediated uptake of LDL or transferrin. While pinocytosis/exocytosis is potentially bidirectional, k up is a fractional rate of "net" movement (thus smaller in magnitude than the 'real' unidirectional uptake rate) from the plasma into the sorting endosomes where IgG binds FcRn according to its binding affinity (equilibrium binding constant; K D ) in an acidic endosomal environment [25]. Considering known aspects of receptor-ligand interaction and the law of mass action, equilibrium is established within the endosome between free and FcRnbound IgG.…”

“…Therefore, the plasma concentration is not identical to but is an index for endosomal unbound IgG concentration (see Results and Discussion). FcRn-bound IgG is recycled to the plasma at a rate controlled by a fractional endosomal recycling rate (k rec ) whereas unbound IgG is degraded [25][26][27] at a rate controlled by a fractional endosomal degradation rate (k deg ). The distribution of IgG between the vascular and extravascular compartments was assumed to be FcRn-independent and is controlled by fractional intercompartmental distribution rates (k 12 and k 21 ).…”

Human FcRn can mediate the transport across intestinal mucosal barrier and prolong the half-life of rabbit IgG in vivo

“…In addition to its crucial roles in exerting IgG transportation, FcRn has other various functions. Professional APCs (monocytes, macrophages and some dendritic cell (DCs) subsets) express FcRn (Zhu et al 2001) and are in charge of carrying the antigen across the gastrointestinal barrier (Yoshida et al 2004), controlling and prolonging the life of IgG (Ward et al 2003) and combining with albumin, controlling the transportation, circulation and life of albumin (Chaudhury et al 2003;Kim 2005;Andersen et al 2006). The process of FcRn combining with IgG requires strict pH dependency, i.e., when in pH 5.0-6.0, FcRn and IgG combine via nanomolar appetency.…”