Antigen-Specific Antibody Glycosylation Is Regulated via Vaccination

Abstract

Antibody effector functions, such as antibody-dependent cellular cytotoxicity, complement deposition, and antibody-dependent phagocytosis, play a critical role in immunity against multiple pathogens, particularly in the absence of neutralizing activity. Two modifications to the IgG constant domain (Fc domain) regulate antibody functionality: changes in antibody subclass and changes in a single N-linked glycan located in the CH2 domain of the IgG Fc. Together, these modifications provide a specific set of instructions to the innate immune system to direct the elimination of antibody-bound antigens. While it is clear that subclass selection is actively regulated during the course of natural infection, it is unclear whether antibody glycosylation can be tuned, in a signal-specific or pathogen-specific manner. Here, we show that antibody glycosylation is determined in an antigen- and pathogen-specific manner during HIV infection. Moreover, while dramatic differences exist in bulk IgG glycosylation among individuals in distinct geographical locations, immunization is able to overcome these differences and elicit antigen-specific antibodies with similar antibody glycosylation patterns. Additionally, distinct vaccine regimens induced different antigen-specific IgG glycosylation profiles, suggesting that antibody glycosylation is not only programmable but can be manipulated via the delivery of distinct inflammatory signals during B cell priming. These data strongly suggest that the immune system naturally drives antibody glycosylation in an antigen-specific manner and highlights a promising means by which next-generation therapeutics and vaccines can harness the antiviral activity of the innate immune system via directed alterations in antibody glycosylation in vivo.

The immunoglobulin G1 N-glycan composition affects binding to each low affinity Fc γ receptor

“…There is growing evidence that the IgG1 Fc N-glycan composition changes in response to disease. [44][45][46][47][48] Our data indicate variations in Fc N-glycan composition profiles alter relative FcgR binding affinities. Considering the tissue-specific expression profile for the FcgRs, 3 changes to the IgG1 Fc N-glycan composition therefore have the potential to direct which leukocyte populations are affected and, as a result, direct the body's response to infection.…”

Innate transcriptional effects by adjuvants on the magnitude, quality, and durability of HIV envelope responses in NHPs

“…Systems serological analyses were performed as previously described, 44,46,47 and are also detailed in the supplemental Methods.…”

“…[31][32][33][34][35][36] Immune-stimulating complexes (ISCOMs), composed of saponins, cholesterol, and phospholipids, are a distinct class of adjuvant that act through both inflammatory and IFN pathways to enhance Ag uptake by DCs. [37][38][39][40][41] Recent studies have used systems serology analyses to qualitatively assess antibody responses based on Fc-mediated effector functions, [42][43][44][45][46][47] which have been found to play a role in protection against simian immunodeficiency virus (SIV) 48 and HIV. 4 To assess the mechanisms by which adjuvants and vaccines mediate such effector functions, transcriptional profiling has been used in mouse models, [49][50][51][52] as well as in humans to define biomarkers to predict protection.…”

A Functional Role for Antibodies in Tuberculosis

“…In HIV infection (Ackerman et al, 2013) and autoimmune disease (Anthony et al, 2011; Jefferis, 2009; Malhotra et al, 1995; Parekh et al, 1989), antigen-specific Abs are differentially glycosylated as a function of disease state and treatment status (Ackerman et al, 2013; Gardinassi et al, 2014; Ho et al, 2014; Vidarsson et al, 2014). Moreover, recent data suggest the existence of distinct Ab glycosylation patterns between different antigen specificities (Mahan et al, 2016). Thus, Ab glycosylation differences may reflect differential B cell priming (Mahan et al, 2016; Selman et al, 2012) aimed at directing optimized pathogen- or antigen-specific clearance activity.…”

“…These Fc effector functions are regulated immunologically via two features of the Ab Fc domain: 1) through Fc class-switch recombination selecting different isotypes (i.e., IgG, IgM, IgA, IgD, and IgE) and/or subclasses (e.g., IgG1, 2, 3, 4) and 2) the post-translational addition of distinct glycan species on the Fc domain of antibodies, specifically at asparagine 297 on IgG (Vidarsson et al, 2014). In particular, Ab glycosylation varies with age, sex, disease state, treatment, infection, and vaccination which likely reflect the highly sensitive and dynamic processes that actively alter Ab effector function during an inflammatory response (Ackerman et al, 2013; Gardinassi et al, 2014; Ho et al, 2014; Mahan et al, 2016; Parekh et al, 1989). …”