The Neonatal Fc Receptor (FcRn): A Misnomer?

Abstract

Antibodies are essential components of an adaptive immune response. Immunoglobulin G (IgG) is the most common type of antibody found in circulation and extracellular fluids. Although IgG alone can directly protect the body from infection through the activities of its antigen binding region, the majority of IgG immune functions are mediated via proteins and receptors expressed by specialized cell subsets that bind to the fragment crystallizable (Fc) region of IgG. Fc gamma (γ) receptors (FcγR) belong to a broad family of proteins that presently include classical membrane-bound surface receptors as well as atypical intracellular receptors and cytoplasmic glycoproteins. Among the atypical FcγRs, the neonatal Fc receptor (FcRn) has increasingly gained notoriety given its intimate influence on IgG biology and its ability to also bind to albumin. FcRn functions as a recycling or transcytosis receptor that is responsible for maintaining IgG and albumin in the circulation, and bidirectionally transporting these two ligands across polarized cellular barriers. More recently, it has been appreciated that FcRn acts as an immune receptor by interacting with and facilitating antigen presentation of peptides derived from IgG immune complexes (IC). Here we review FcRn biology and focus on newer advances including how emerging FcRn-targeted therapies may affect the immune responses to IgG and IgG IC.

Keywords: FcRn; IgG; IgG immune complex (IgG-IC); albumin (ALB); immunity; therapeutic.

Figure 1

FcRn structure and ligand binding. (A) Human FcRn heavy chain (green) is non-covalently associated with beta-2 microglobulin (β₂m, gray). (B) Topological representation of membrane associated FcRn in the standing up position. Bound albumin (magenta) and a monomeric IgG1 (blue) are modeled onto the structure of FcRn in complex with the Fc part of IgG^MST and albumin. In this orientation possible clashes may occur between the Fab arms of the IgG and the membrane. For simplicity the figures depict stoichiometric FcRn and IgG ratio of one to one. (C) Topological representation of membrane associated FcRn in the lying down position. This orientation accommodates Fab arms of IgG yet it potentially confines the albumin binding site. (D) Topological representation of membrane associated FcRn bound to albumin and IgG in complex with a small antigen [guinea fowl lysozyme (orange)]. The reclined orientation of FcRn on the surface of the endosomal membrane may most proficiently accommodate both ligands. Binding of large IgG IC (not depicted) might impose a lying down FcRn position. The figures were made using Adobe Illustrator, PyMol and the crystal structure data from: FcRn in complex with the Fc part of IgG^MST and albumin (23), a full-length human IgG1 antibody (24), and guinea fowl lysozyme (25), PDB IDs 4N0U, 1HZH and 1FBI respectively.

Figure 2

Lessons from conventional and conditional FcRn deficient mouse models. Phenotypic observations reported in mice deficient for FcRn (Fcgrt^−/−). Blue boxes denote FcRn-affected function and green boxes denote pathophysiological consequences.

Figure 3

FcRn mediates bidirectional transport and immune response to IgG and IgG immune complexes in the gut. (1) The pH of the mucosal surface of the proximal intestine can be slightly acidic, such that FcRn can bind maternal IgG and IgG IC already at the cell surface, and transcytose these to the basolateral side. (2) APC such as DC, can bind and actively internalize IgG IC via FcγR. (3) FcRn in APC assists in antigen processing and delivery of the IgG IC to antigen loading compartments where peptides derived from these complexes can be loaded onto MHC II for presentation to CD4⁺ T cells. (4) In early life, presentation of antigen-derived peptide on MHC II in presence of other maternal milk-derived factors provides (5) tolerogenic environment to CD4⁺ T cells. In these instances, FcRn expression by APC is crucial for induction of CD4⁺Foxp3⁺ regulatory T cells (Treg). (6) In adulthood, during infection, pathogen derived antigens bound by lumenal IgG will be transported across mucosal membrane in an FcRn-dependent manner and (7) delivered to APC, which process and present antigens, (8) for subsequent activation of immune responses.

Figure 4

FcRn in the liver is essential for vectorial delivery of albumin into the blood stream. (1) Hepatocytes are polarized epithelial cells of which the apical side (red) faces the bile duct, and the basolateral side (black) faces the fenestrated sinusoidal endothelium. The sinusoidal endothelium is populated by liver specific macrophages called Kupffer cells. Albumin is produced solely by hepatocytes. (2) FcRn in hepatocytes is required for delivery of newly synthesized albumin to the basolateral side of the cells, and subsequent secretion of albumin to the blood stream (left) (3) Absence of FcRn expression in hepatocytes results in increased albumin levels in the bile, its intracellular accumulation and lower circulating albumin levels (right). For simplicity, FcRn-mediated albumin recycling in hepatocytes is not depicted.

Figure 5

Emerging roles of FcRn in cancer. (1) During the process of oncogenesis, cells can lose or downregulate FcRn expression. In these instances, tumor cells will be unable to recycle albumin upon its internalization. Albumin will instead be degraded, providing nutrients to the tumor and promoting tumor growth. (2) Absence of FcRn in APC may decrease the basal cytotoxic tone (such as IL-12 production) resulting in diminished numbers and function of either NK or CD8⁺ T cells in tissues, generating a tumor-prone environment. (3) Released tumor antigens can be bound by antibodies and internalized by APC through FcγRs. Presence of FcRn in these cells is important for (4) the subsequent sorting and efficient processing of IgG IC in antigen loading compartments where tumor-derived peptides are loaded onto MHC I for cross-presentation to (5) cytotoxic CD8⁺ T cells. Activated tumor specific CD8⁺ T cells will (6) effectively target cancerous cells for destruction.