IgG Subclasses and Allotypes: From Structure to Effector Functions

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.

Rapid, automated characterization of disulfide bond scrambling and IgG2 isoform determination

“…High sequence conservation near the inter-chain cysteines, regardless of allotype, implies that this collection of signature peptides is widely applicable to other human IgG2s. 5,6 The peptides described here do not support discernment between different cross-linking configurations of nearby cysteines (i.e., canonical vs. scrambled hinge disulfides). For example, disulfide bond variants within the lower hinge region of the native B isoform reported elsewhere would not be differentiated using this method.…”

“…4 The four IgG subclasses (IgG1, IgG2, IgG3, and IgG4) differ structurally with respect to their conserved amino acid sequences, the length of the core hinge region, and the number and configurations of inter-chain disulfide bonds. 5,6 The HC and LC are linked by one disulfide bond, and the HCs are linked by two (for IgG1 and IgG4) or four (for IgG2) disulfide bonds located in the hinge region. The inter-chain disulfide bond configuration and non-covalent inter-domain interactions modulate the higher-order structures of each IgG subclass.…”

Novel human anti-claudin 1 mAbs inhibit hepatitis C virus infection and may synergize with anti-SRB1 mAb

“…The selected scFvs were converted into fully human IgG4 because this isotype was shown to have reduced complement and cell-mediated cytotoxicity, while displaying long half-life (Vidarsson et al, 2014). All resulting human mAbs conserved their specificity of binding to cell-displayed CLDN-1, with the majority of them showing apparent affinities in the low-nanomolar range, and did not show cytotoxic activity when incubated with human hepatoma cells in vitro.…”

Nanobodies: Chemical Functionalization Strategies and Intracellular Applications

“…IgGs are the predominant isotype of immunoglobulins and consist of two identical heavy and two identical light chains that are covalently linked through disulfide bonds 1. The antigen is recognized through an interplay between the variable N‐terminal domains of the heavy (V H ) and the light (V L ) chain and six CDRs (Figure 1 a) 8.…”

“…Immunoglobulin G (IgG), a 150 kDa protein consisting of two heavy and two light chains is the predominant antibody type found in nature 1. Since antibodies were used for the detection of rhesus factor immunization and to quantify the amount of insulin present in blood plasma, uncountable analytical applications have been developed 2.…”