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Review
. 2009:103:77-115.
doi: 10.1016/S0065-2776(09)03004-1.

Chapter 4: Multitasking by exploitation of intracellular transport functions the many faces of FcRn

E Sally Ward  1 , Raimund J Ober
Affiliations
Review

Chapter 4: Multitasking by exploitation of intracellular transport functions the many faces of FcRn

E Sally Ward et al. Adv Immunol. 2009.

Abstract

The MHC Class I-related receptor, FcRn, transports antibodies of the immunoglobulin G (IgG) class within and across a diverse array of different cell types. Through this transport, FcRn serves multiple roles throughout adult life that extend well beyond its earlier defined function of transcytosing IgGs from mother to offspring. These roles include the maintenance of IgG levels and the delivery of antigen in the form of immune complexes to degradative compartments within cells. Recent studies have led to significant advances in knowledge of the intracellular trafficking of FcRn and (engineered) IgGs at both the molecular and cellular levels. The engineering of FcRn-IgG (or Fc) interactions to generate antibodies of increased longevity represents an area of active interest, particularly in the light of the expanding use of antibodies in therapy. The strict pH dependence of FcRn-IgG interactions, with binding at pH 6 that becomes essentially undetectable as near neutral pH is approached, is essential for efficient transport. The requirement for retention of low affinity at near neutral pH increases the complexity of engineering antibodies for increased half-life. Conversely, engineered IgGs that have gained significant binding for FcRn at this pH can be potent inhibitors of FcRn that lower endogenous IgG levels and have multiple potential uses as therapeutics. In addition, molecular studies of FcRn-IgG interactions indicate that mice have limitations as preclinical models for FcRn function, primarily due to cross-species differences in FcRn-binding specificity.

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Figures

Figure 4.1
Figure 4.1
Structure (α-carbon trace) of the Fc region of human IgG1 (Deisenhofer, 1981) with the location of the key residues that are involved in binding to mouse or human FcRn indicated. The same residues of mouse IgG1 are also involved in FcRn binding, except that Tyr436 is replaced by histidine. The structure was drawn using Rasmol (courtesy of Roger Sayle, Bioinformatics Research Institute, University of Edinburgh).
Figure 4.2
Figure 4.2
Structure (α-carbon trace) of rat FcRn with the location of the key residues that are involved in binding to rat IgG2a indicated (Martin et al., 2001). The structure was drawn using Rasmol (courtesy of Roger Sayle, Bioinformatics Research Institute, University of Edinburgh).
Figure 4.3
Figure 4.3
Schematic representation of FcRn-mediated recycling of IgG in a polarized cell such as an endothelial cell. IgGs are taken into the cell by fluid phase and enter early endosomes. The pH of the early endosome is permissive for FcRn binding, and binding of the IgG to FcRn results in recycling (or transcytosis, not shown) and salvage from lysosomal degradation. Conversely, unbound IgG enters the lysosome and is degraded.
Figure 4.4
Figure 4.4
Individual frames from live-cell imaging of sorting endosomes in human FcRn (hFcRn)–GFP-transfected endothelial (HMEC-1) cells pulse-chased with (A, B) Alexa 546-labeled human IgG1 (hIgG1) or (C, D) Alexa 546-labeled H435A (His435 to Ala) mutant that binds with immeasurably low affinity to human FcRn (Firan et al., 2001). Cells were pulsed with labeled IgG and subsequently chased in medium at 37 °C. Images of live cells were acquired and processed as described in Ober et al. (2004b). Arrowheads indicate tubules (FcRn+IgG+ for A, B, FcRn+ only for C, D) and in (A) the tubule separates from the endosome at ∼ 20 s. The first frame for each dataset is arbitrarily labeled 0 s, although the frames shown were taken at different times after the start of the chase period. Bar = 1 μm.
Figure 4.5
Figure 4.5
Cytosolic tail sequences of FcRn from different species (Adamski et al., 2000; Ahouse et al., 1993; Kacskovics et al., 2000, 2006; Kandil et al., 1995; Mayer et al., 2002; Schnulle and Hurley, 2003; Simister and Mostov, 1989; Story et al., 1994). Identity is indicated by red, and the first residue of the sequence corresponds to residue 301 of mouse/rat FcRn. The consensus sequence is also shown, with the tryptophan (W311) and dileucine (L322, L323) motifs that are important for intracellular trafficking indicated in blue.
Figure 4.6
Figure 4.6
Enhancement of clearance of injected wild-type IgG by an Abdeg (Vaccaro et al., 2005). Mice were injected with 125I-labeled wild-type human IgG1, and injected with 500 μg wild-type human IgG1, 200 or 500 μg Abdeg (MST-HN mutant) 72 h later (indicated by arrow). Levels of remaining 125I labeled IgG were determined at the indicated times. Error bars indicate standard deviations. * Indicates that data for these time points for mice treated with 500 or 200 μg Abdeg are significantly different.
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