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Review
. 2014 Oct 20:5:520.
doi: 10.3389/fimmu.2014.00520. eCollection 2014.

IgG subclasses and allotypes: from structure to effector functions

Gestur Vidarsson  1 , Gillian Dekkers  1 , Theo Rispens  2
Affiliations
Review

IgG subclasses and allotypes: from structure to effector functions

Gestur Vidarsson et al. Front Immunol. .

Abstract

Of the five immunoglobulin isotypes, immunoglobulin G (IgG) is most abundant in human serum. The four subclasses, IgG1, IgG2, IgG3, and IgG4, which are highly conserved, differ in their constant region, particularly in their hinges and upper CH2 domains. These regions are involved in binding to both IgG-Fc receptors (FcγR) and C1q. As a result, the different subclasses have different effector functions, both in terms of triggering FcγR-expressing cells, resulting in phagocytosis or antibody-dependent cell-mediated cytotoxicity, and activating complement. The Fc-regions also contain a binding epitope for the neonatal Fc receptor (FcRn), responsible for the extended half-life, placental transport, and bidirectional transport of IgG to mucosal surfaces. However, FcRn is also expressed in myeloid cells, where it participates in both phagocytosis and antigen presentation together with classical FcγR and complement. How these properties, IgG-polymorphisms and post-translational modification of the antibodies in the form of glycosylation, affect IgG-function will be the focus of the current review.

Keywords: Fc receptors; IgG; genetic; glycosylation; immunoglobulin G; neonatal Fc receptor; polymorphism.

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Figures

Figure 1
Figure 1
(A) Crystal structure of an human IgG1 molecule (1HZH) viewed from two different angles, demonstrating the flexibility of the two Fab fragments with respect to each other and the Fc tail. The binding location for FcγR, binding IgG asymmetrically in a 1:1 configuration (–49), is indicated by the blue circle (lower hinge, upper CH2) on the left, and the location of the binding motifs for FcRn, TRIM21, and the potential site for binding of DC-SIGN on the right (intersection of CH2 and CH3). FcRn, and the potential binding site of DC-SIGN bind IgG in a 2:1 configuration (–52), respectively, while a dimer of TRIM21 binds IgG in a 1:1 configuration (53). The N-linked glycan at position 297 attached to each of the heavy chains is shown on the right. (B) The N-linked glycan found at position 297 can be found as a core structure, common to all IgG found in human beings and rodents (core structure indicated with a red dashed line), but can be found with either an addition of fucose, bisecting N-acetylglucosamine (GlcNAc), one or two galactose, and one or two sialic acid residues.
Figure 2
Figure 2
The schematic layout of the IgG subclasses and isomers thereof. (A) The IgG subclasses, indicating how the different heavy and light chains are linked, the length of the hinge, and the number of disulfide bridges connecting the two heavy chains. For orientation, and comparison with Figure 1, the location of the hinge, CH2, and CH3 domains are shown. The classical A/A isoform of IgG2 with four different disulfide bridges between the two heavy chains is depicted here, but in (B) the B/B form, with only two disulfide bridges and alternative linkages of the light chain to the heavy chain form is shown, together with the intermediate A/B form. (C) Isomers of IgG4 resulting in half-molecule exchange. On the far left and far right, two classically depicted IgG4 clones in slightly different colors are shown just after secretion from B-cells. These are connected with two inter-chain disulfide bridges. However, these are in fact in equilibrium where these are reduced creating forms without covalent linkages between the symmetric molecules. This form can either revert back to covalently linked form or swap heavy chains in a stochastic process with that of neighboring IgG4 molecule creating a asymmetric bispecific IgG4 (bottom middle) that is also in flux, reverting into covalently linked IgG4 (top, middle). By this process, most IgG4 found in human beings (expressing the IgG4-R409 allotype, see text for more details and Figure 3) are monovalent-bispecific molecules.
Figure 3
Figure 3
IgG subclasses and IgG allotypes. (A) All differences between the IgG isotypes depicted schematically according to their localization (numbered below a graphical representation of the gene) in the different domains and exons depicted above the sequence. Bold underlined numbers (EU numbering) contain isoallotypic variant at that position. Amino acids depicted in bold varies from the other subclasses, but amino acids depicted in italics are present in two subclasses. The green boxed amino acids numbers are residues involved in binding to C1q, in red amino acids involved in FcγR binding, and in blue residues involved in binding to FcRn. “-“ instead of a letter for amino acid stands for the missing G236 residue in IgG2. (B) The amino acid variation found within IgG1, IgG2, and IgG4 allotypes, and (C) among the IgG3 allotypes. The presence or absence of the two kinds of IgG3-hinge exons (a, and b) are indicated by “+” or “–” in (C). For (B,C), amino acids in bold are those unique for subclass or allotype, and those underlined isoallotypes, as this amino acid is also found in other subclasses at this position. The unique IMGT numberings and a representative sequence accession number are indicated on the right. For some of the allotypes, the IMGT numberings are represented by several different genes, but encoding for identical hypothetical proteins.
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