Modulating Antibody Functionality in Infectious Disease and Vaccination

Abstract

Induction of pathogen-specific binding antibodies has long been considered a signature of protective immunity following vaccination and infection. The humoral immune response is a complex network of antibodies that target different specificities and drive different functions, collectively acting to limit and clear infection either directly, via pathogen neutralization, or indirectly, via pathogen clearance by the innate immune system. Emerging data suggest that not all antibody responses are equal, and qualitative features of antibodies may be key to defining protective immune profiles. Here, we review the most recent advances in our understanding of protective functional antibody responses in natural infection, vaccination, and monoclonal antibody therapeutics. Moreover, we highlight opportunities to augment or modulate antibody-mediated protection through enhancement of antibody functionality.

Keywords: ADCC; Fc receptors; HIV; antibodies; antibody glycosylation; vaccination.

Copyright © 2016. Published by Elsevier Ltd.

Figures

Figure 1.. Antibody Affinity for FcRs and FcR Expression on Immune Cells.

Antibody isotypes and subclasses have different affinities for various FcRs. The FcγR family of receptors binds IgG, FcεRI binds IgE, and Fc/R binds IgA. Within IgG, IgG1 and IgG3 bind to all FcγRs with higher affinity compared with IgG2 and IgG4, and IgG2 does not bind FcγRI. Cellular expression of the different FcRs also varies on innate immune cells. Monocytes and macrophage express the high-affinity FcγRI, high levels of the FcγRIIA, low levels of FcγRIIB, and low levels of FcγRIIIA. Dendritic cells (DCs) express FcγRI, FcγRIIA, and FcγRIIB, as well as the type II Fc receptor DC-SIGN. NK cells predominantly express activating FcγRIIIA, although polymorphisms in the FCGR2C gene allow for FcγRIIC expression on NK cells a subset of individuals. Neutrophils express high levels of the GPI-linked FcγRIIIB, low levels of FcγRIIA, and can induce expression of the high-affinity FcγRI. Eosinophils, basophils, and mast cells predominantly express the FcεR to bind IgE, but also express FcγRIIA and FcγRIIB, and mast cells can induce FcγRI. B cells express only one FcγR, the inhibitory FcγRIIb, which provides negative feedback to the B cell, and plays a key role in immune tolerance.

Figure 2.. IgG Glycan Substructures.

There are 36 possible biantennary glycan structures present on each heavy chain of IgG, and these can be broadly divided into agalactosylated (G0) structures, galactosylated nonsialylated (G1/G2), and sialylated structures. Agalactosylated IgG are more associated with inflammatory activity, whereas sialylated IgG are associated with anti-inflammatory activity. The presence or absence of fucose (fucosylated or afucosylated, respectively) or the presence or absence of a bisecting GlcNAC modulate interactions with FcγRIIIA that impact induction of FcγRIIIA-dependent effector functions, with afucosylated and bisected IgG having the highest affinity for FcγRIIIA.

Figure I.

Natural Modulation of Antibody Functionality.