The Ligands for Human IgG and Their Effector Functions

Abstract

Activation of the humoral immune system is initiated when antibodies recognize an antigen and trigger effector functions through the interaction with Fc engaging molecules. The most abundant immunoglobulin isotype in serum is Immunoglobulin G (IgG), which is involved in many humoral immune responses, strongly interacting with effector molecules. The IgG subclass, allotype, and glycosylation pattern, among other factors, determine the interaction strength of the IgG-Fc domain with these Fc engaging molecules, and thereby the potential strength of their effector potential. The molecules responsible for the effector phase include the classical IgG-Fc receptors (FcγR), the neonatal Fc-receptor (FcRn), the Tripartite motif-containing protein 21 (TRIM21), the first component of the classical complement cascade (C1), and possibly, the Fc-receptor-like receptors (FcRL4/5). Here we provide an overview of the interactions of IgG with effector molecules and discuss how natural variation on the antibody and effector molecule side shapes the biological activities of antibodies. The increasing knowledge on the Fc-mediated effector functions of antibodies drives the development of better therapeutic antibodies for cancer immunotherapy or treatment of autoimmune diseases.

Keywords: Antibodies; Fc effector molecules; IgG; allotypes; glycosylation.

Figure 1

Structural variation of immunoglobulin G subclasses. A structural representation of the immunoglobulin G (IgG) subclasses and the variation within these subclasses, including allotype variation, hinge variation, and glycosylation. The variation originating from allotypic polymorphisms in the immunoglobulin heavy gamma (IGHG) constant domain is indicated by blue stars. Except for the star representing the variation in hinge length between IgG3 allotypes, each blue star indicates amino acid variation at one particular residue in the constant domain. Fab glycosylation is indicated and is present in 5–30% of antibodies in serum, depending on subclass and antigen specificity. The glycoform of the N297 Fc glycan is highly variable, for which the frequency of each glycan moiety on IgG antibodies in human serum is indicated.

Figure 2

Interaction of IgG with Fc effector molecules. Schematic representation of IgG- and all Fc-engaging molecules (Complement component (C1q), Fc gamma receptors (FcγR), the Neonatal Fc receptor (FcRn), Tripartite motif 21 (Trim21), and Fc receptor-like (FcRL) molecules 4 and 5) through which antibodies exert their biological activity. For each ligand the binding site on IgG and the stoichiometry of the interaction with IgG is indicated. The red stars represent the binding site of IgG on the Fc effector molecules.