The immunologic functions of the neonatal Fc receptor for IgG

Abstract

Careful regulation of the body's immunoglobulin G (IgG) and albumin concentrations is necessitated by the importance of their respective functions. As such, the neonatal Fc receptor (FcRn), as a single receptor, is capable of regulating both of these molecules and has become an important focus of investigation. In addition to these essential protection functions, FcRn possesses a number of other functions that are equally as critical and are increasingly coming to attention. During the very first stages of life, FcRn mediates the passive transfer of IgG from mother to offspring both before and after birth. In the adult, FcRn regulates the persistence of both IgG and albumin in the serum as well as the movement of IgG, and any bound cargo, between different compartments of the body via transcytosis across polarized cells. FcRn is also expressed by hematopoietic cells; consistent with this, FcRn regulates MHC class II presentation and MHC class I cross-presentation by dendritic cells. As such, FcRn plays an important role in immune surveillance throughout adult life. The increasing appreciation for FcRn in both homeostatic and pathological conditions is generating an intense interest in the potential for therapeutic modulation of FcRn binding to IgG and albumin.

Fig 1

Crystal structure of human FcRn. FcRn is a heterodimer consisting of a MHC class I-like heavy chain (blue) that is non-covalently associated with β2-microglobulin (β2m, green). Critical residues for the interaction with IgG molecules are indicated in yellow. The binding of albumin to FcRn (marked in red) occurs at a distinct site from that of IgG, with the conserved histidine 166 as a critical residue for pH-dependent binding to albumin. Adapted from [22]

Fig 2

FcRn-mediated IgG transport and antigen retrieval across the intestinal epithelial barrier. FcRn in enterocytes mediates the transcytosis of IgG molecules from the basolateral side into the gastrointestinal lumen. Following formation of antigen-IgG immune complexes, FcRn is then able to bind these immune complexes and transcytose them back to the basolateral side, where the IgG-antigen complex is delivered to antigen-presenting cells (APC) in the lamina propria. Antigen-loaded APCs then migrate to draining lymph nodes and initiate a T-cell response.

Fig 3

FcRn-dependent cross-presentation of immune complexes. Following internalization by surface Fcγ receptors, FcRn regulates the intracellular sorting of IgG ICs into a Rab27a, vacuolar ATPase, Sec61, TAP, gp91phox, and MHC class I-containing acidic phagosome that allows for cross-presentation. In the absence of FcRn expression or the ability of the IgG to bind to FcRn, CD8⁻CD11b⁺CD11c⁺ inflammatory dendritic cells are disabled in their ability to properly participate in cross-presentation. Adapted from [76]