IgG subclasses and allotypes: from structure to effector functions.

Gestur Vidarsson,Theo Rispens,Gillian Dekkers

doi:10.3389/fimmu.2014.00520

Gestur Vidarsson, Theo Rispens + Show 1 more

Open Access

https://doi.org/10.3389/fimmu.2014.00520

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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.

Highlights

Immunoglobulin G (IgG) is one of the most abundant proteins in human serum, accounting for about 10–20% of plasma protein
They are more than 90% identical on the amino acid level, each subclass has a unique profile with respect to antigen binding, immune complex formation, complement activation, triggering of effector cells, half-life, and placental transport
CONCLUDING REMARKS Immunoglobulin G-mediated responses diverge and depend largely on the type of secondary immune responses, which in turn depend on the type of antigen

Summary

INTRODUCTION

Immunoglobulin G (IgG) is one of the most abundant proteins in human serum, accounting for about 10–20% of plasma protein. The unique S228 in the core hinge of IgG4 allows formation of the intra-chain isomer, and R409 (rather than the equivalent lysine in IgG1) results in weaker CH3–CH3 interactions (Figure 3A) [77, 78] Both determinants appear to be required to observe Fab arm exchange in vivo [74] and have been observed for the therapeutic IgG4 antibody natalizumab [79]. This includes on the number of unknown variants, the frequency by which they appear within and between populations This can have functional consequences, on expression levels [21], half-life, FcγR binding [antibody-dependent cell-mediated cytotoxicity (ADCC), ADCP], tendency to form oligomers [99] and activate complement, and influence on immunogenicity – again within and between populations – and, have important consequences for antibody-mediated immunotherapies. Binding to DC-SIGN sialylated antibodies has been suggested to have strong immunomodulatory function as described below (see DC-SIGN)

EFFECTOR MECHANISMS

Findings

ALTERNATIVE RECEPTORS FOR IgG