Signaling by Antibodies: Recent Progress

Abstract

IgG antibodies mediate a diversity of immune functions by coupling of antigen specificity through the Fab domain to signal transduction via Fc-Fc receptor interactions. Indeed, balanced IgG signaling through type I and type II Fc receptors is required for the control of proinflammatory, anti-inflammatory, and immunomodulatory processes. In this review, we discuss the mechanisms that govern IgG-Fc receptor interactions, highlighting the diversity of Fc receptor-mediated effector functions that regulate immunity and inflammation as well as determine susceptibility to infection and autoimmunity and responsiveness to antibody-based therapeutics and vaccines.

Keywords: Fc receptors; IgG; effector function; immunity; immunomodulation; inflammation.

Figure 1. Overview of the structural characteristics of IgG (A) and FcγRs (B)

IgG antibodies comprise two identical heavy and light chains linked by inter-chain disulfide bonds. At the core of the Fc domain, an N-linked glycan structure is conjugated at a highly-conserved site at the CH2 domain (Asn297 for human IgG1), which regulates the conformation of the Fc domain and determines binding to Type I and Type II FcγRs. The structure and composition of the Fc-associated glycan can be dynamically regulated through the addition of specific sugar moieties to the core glycan structure (highlighted in the red box), which in turn determines the binding affinity of the Fc domain for Type I and Type II FcγRs. Despite their common property to interact with the IgG Fc, Type I and Type II FcγRs present distinct structural and functional differences and have differential capacity to induce diverse immunomodulatory consequences that affect several aspects of innate and adaptive immunity.