A Temporal Model of Human IgE and IgG Antibody Function

Abstract

The diversity of the human antibody repertoire that is generated by V(D)J gene rearrangement is extended by nine constant region genes that give antibodies their complex array of effector functions. The application of high throughput sequencing to the study of V(D)J gene rearrangements has led to significant recent advances in our understanding of the antigen-binding repertoire. In contrast, our understanding of antibody function has changed little, and mystery still surrounds the existence of four distinctive IgG subclasses. Recent observations from murine models and from human studies of VDJ somatic point mutations suggest that the timing of emergence of cells from the germinal center may vary as a consequence of class switching. This should lead to predictable differences in affinity between isotypes. These differences, and varying abilities of the isotypes to fix complement and bind FcRs, could help coordinate the humoral defenses over the time course of a response. We therefore propose a Temporal Model of human IgE and IgG function in which early emergence of IgE sensitizes sentinel mast cells while switching to IgG3 recruits FcγR-mediated functions to the early response. IgG1 then emerges as the major effector of antigen clearance, and subsequently IgG2 competes with IgG1 to produce immune complexes that slow the inflammatory drive. Persisting antigen may finally stimulate high affinity IgG4 that outcompetes other isotypes and can terminate IgG1/FcγR-mediated activation via the inhibitory FcγRIIB. In this way, IgG antibodies of different subclasses, at different concentrations and with sometimes opposing functions deliver cohesive, protective immune function.

Low immunoglobulin E flags two distinct types of immune dysregulation

“…IgG3 has distinct roles from other IgG subclasses. It has a much higher turnover than the other subclasses with a half-life of 7 versus 21 days, it is the best activator of complement and, together with IgE, is the first of the subclasses to appear in an immune response [17]. Thus, IgG3 joins the IgM-dependent early defence to bind and clear foreign antigens.…”

The Solution Structures of Two Human IgG1 Antibodies Show Conformational Stability and Accommodate Their C1q and FcγR Ligands

“…The precise role of the four IgG subclasses in the immune response is unclear. A recent temporal model suggests that the different properties of the IgG subclasses, their concentrations, and their emergence at different stages facilitate a more cohesive immune response (46). An understanding of the distinct properties of the IgG subclasses is desired; we now have complete scattering analyses for human IgG1 and IgG4.…”

Zaburzenia tarczycy związane z immunoglobuliną G4 — wyzwanie diagnostyczne i wyniki kliniczne

“…The differential ratios of these three antibodies determine the pattern of immune response. Ig G4 is believed to appear late as a part of the humoral immune process, only on persistent antigenaemia, having a primary role in dampening down inflammation by helping to curtail FcR-mediated processes [6,7]. The circulating half-life of Ig G4 is 21 days.…”

“…[4,5]. It has been suggested that IgG3 along with Ig E appears earliest in the immune response, followed by Ig G2 and G1 [6]. The differential ratios of these three antibodies determine the pattern of immune response.…”