Understanding the role of antibody glycosylation through the lens of severe viral and bacterial diseases

Abstract

Abundant evidence points to a critical role for antibodies in protection and pathology across infectious diseases. While the antibody variable domain facilitates antibody binding and the blockade of infection, the constant domain (Fc) mediates cross talk with the innate immune system. The biological activity of the Fc region is controlled genetically via class switch recombination, resulting in the selection of distinct antibody isotypes and subclasses. However, a second modification is made to all antibodies, via post-translational changes in antibody glycosylation. Studies from autoimmunity and oncology have established the role of immunoglobulin G (IgG) Fc glycosylation as a key regulator of humoral immune activity. However, a growing body of literature, exploring IgG Fc glycosylation through the lens of infectious diseases, points to the role of inflammation in shaping Fc-glycan profiles, the remarkable immune plasticity in antibody glycosylation across pathogen-exposed populations, the canonical and noncanonical functions of glycans and the existence of antigen-specific control over antibody Fc glycosylation. Ultimately, this work provides critical new insights into the functional roles for antibody glycosylation as well as lays the foundation for leveraging antibody glycosylation to drive prevention or control across diseases.

Keywords: Fc; antibody; glycosylation; humoral immunity; infectious disease.

Fig. 1

Structure of IgG and the IgG N-linked glycan. IgG molecules have a single N-linked glycosylation site at asparagine 297 of each heavy chain. The base glycan structure is pictured, with each of the four variably added glycan moieties present in parentheses.

Fig. 2

Potential roles for IgG Fc sialylation in driving the evolution of higher avidity and affinity antibody responses. Lofano et al. demonstrate that sialylated immune-complexes (ICs) accelerate antigen delivery to the germinal center in a complement-dependent manner, resulting in the generation of high avidity antibodies. While the pictured model implicates noncognate B cells in improved antigen deposition in the germinal center, other immune cell types expressing complement receptors, including subcapsular sinus macrophages, may also facilitate improved antigen delivery. Wang et al. demonstrate that within the germinal center, sialylated IgG antibodies bind CD23 present on B cells, increasing FcγRIIb surface expression and thus increasing the threshold for B cell receptor (BCR) signaling. This modulation of the germinal center reaction results in the generation of broadly neutralizing, high affinity antibodies.

Fig. 3

Potential model by which autoimmune diseases and chronic infections drive inflammatory IgG release. Persistent antigen exposure results in the formation of immune complexes that drive Fcγ receptor-mediated immune activation and proinflammatory cytokine release. Inflammation may then precipitate the conversion of B cells into antibody-secreting plasmablasts tuned to release largely agalactosylated, asialylated IgG, causing a shift to the inflammatory IgG Fc glycosylation profile observed in numerous autoimmune and chronic infectious diseases.