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.

Antibody transcytosis across brain endothelial-like cells occurs nonspecifically and independent of FcRn

“…Although CSF captures the levels of macromolecules in ISF via ISF-to-CSF convective-driven exchange 41 , it also captures the entry of macromolecules across the less restrictive (relative to the BBB 42 ) endothelium and epithelium that forms the blood-CSF barrier (BCSFB). Thus, it is possible that any saturable transcytosis mechanism for IgG may be attributed to the BCSFB 43 , which also expresses FcRn and warrants further examination of its potential role 8 . However, an overlooked observation is that the steady-state CSF-to-serum levels of IgG3 in humans is at the same proportion as the other three IgG subclasses despite a lack of strong FcRn engagement 44 .…”

“…electrostatic adsorption) processes. The mechanisms regulating the preference for luminal or abluminal shuttling by FcRn remain to be determined, but are likely tissue and organ-specific 6,8,9 . Accordingly, FcRn functionality in BECs may not mirror those reported for other endo-or epithelium (e.g.…”

Constitutive accessibility of circulating proteins to hippocampal neurons in physiologically normal rats

“…However, neonatal fragment crystallizable receptor (FcRn), which binds to IgG, was reported to provide a binding site for Alb and be expressed in the BBB endothelia (Pyzik et al, ). FcRn mediates transcytosis across the BBB not only from the brain to the blood, but also from the blood to the brain (Pyzik et al, ; St‐Amour et al, ). However, the trafficking behavior mediated by FcRn has not been examined in the HIP.…”

No evidence for hypogammaglobulinemia in patients with paroxysmal nocturnal hemoglobinuria (PNH) chronically treated with ravulizumab

“…Clearance of IgG is enhanced following administration of high doses of IgG as the FcRndependent regulation of IgG concentrations is a saturable process, whereas IgM, IgA and albumin concentrations remain unaffected. Furthermore, IgG catabolism is enhanced secondary to antibodies demonstrating an increased binding affinity for the FcRn due to competing with endogenous IgG for FcRn binding [28][29][30].…”