B-cell–independent sialylation of IgG

Abstract

IgG carrying terminal α2,6-linked sialic acids added to conserved N-glycans within the Fc domain by the sialyltransferase ST6Gal1 accounts for the anti-inflammatory effects of large-dose i.v. Ig (IVIg) in autoimmunity. Here, B-cell-specific ablation of ST6Gal1 in mice revealed that IgG sialylation can occur in the extracellular environment of the bloodstream independently of the B-cell secretory pathway. We also discovered that secreted ST6Gal1 is produced by cells lining central veins in the liver and that IgG sialylation is powered by serum-localized nucleotide sugar donor CMP-sialic acid that is at least partially derived from degranulating platelets. Thus, antibody-secreting cells do not exclusively control the sialylationdependent anti-inflammatory function of IgG. Rather, IgG sialylation can be regulated by the liver and platelets through the corresponding release of enzyme and sugar donor into the cardiovascular circulation.W hile en route to the plasma membrane as integral membrane proteins or for secretion, glycoproteins exiting the endoplasmic reticulum traverse the cis-, medial-, and trans-Golgi apparatus where the associated N-linked glycans are remodeled into their final form. This classically defined secretory pathway dictates that the glycoform of all glycoproteins produced by a cell is largely determined by the cohort of enzymes within the Golgi and the metabolic circumstances of that specific cell.Protein glycosylation is known to play fundamental roles in all aspects of biology, but has recently gained significant attention in immunology. When administered at high doses, i.v. Ig (IVIg) is an effective anti-inflammatory treatment for autoimmune patients (1). In 2006, it was discovered that the ∼10% of IgG molecules that carry α2,6-linked sialic acids upon the conserved biantennary N-glycans within the Fc domain provided the potent IVIg anti-inflammatory activity in autoimmune disease (2). Indeed, enrichment for the sialylated IgG (sIgG) fraction from IVIg pools increased the efficacy of treatment in mouse models of arthritis 100-fold in an IL-4-dependent fashion through receptors such as CD209 (DC-SIGN) (3, 4). Moreover, it was reported that sialylation of IgG also impacts antibody affinity maturation, although the mechanism underlying this phenomenon remains to be fully elucidated (5). These data indicate that sialylation serves as the mechanism underlying pleotropic IgG function (3,4,6).Epidemiologic analyses published since the reports cited above are consistent with this model. For example, female rheumatoid arthritis patients often go into remission during pregnancy and then relapse following childbirth. Analysis of sIgG levels before, during, and after pregnancy showed that the level of sIgG increases rapidly during pregnancy-induced remission, whereas during periods of exacerbated disease, sIgG is essentially undetectable (7,8). To date, it is unclear whether IgG sialylation patterns precede or result from the inflammatory state, and essentially nothing is known about the regulatory mecha...

Sialylation of N-glycans: mechanism, cellular compartmentalization and function

“…Recent work has demonstrated that activated platelets release the CMP-Sia that serves as the donor for circulating ST6Gal-I, allowing for the remodeling of the glycans of hematopoietic progenitor cells (Lee et al 2014). Additional in vivo support for the biosynthetic role of circulating ST6Gal-I comes from a recent study showing that ST6Gal-I-deficient B cells express IgGs that are modified with α2,6-sialylated glycans and these are synthesized by circulatory ST6Gal-I released from the liver and CMP-Sia from activated platelets (Jones et al 2016).…”

Multi-level glyco-engineering techniques to generate IgG with defined Fc-glycans

“…Furthermore, significant shifts in relative levels have been associated with age (all glycosylation features except fucosylation), infection and pregnancy111213141516. The type of glycosylation is dependent on expression levels of glycosyltransferases and glycosidases in the secretion pathway of the antibody-producing plasma B cell17, except for sialylation which is probably also depended on extracellular sialyltransferase expression in the circulation181920. The degree of fucosylation and bisection of IgG is generally very stable, with ~95% serum IgG being fucosylated and ~15% bisected.…”

Natural killer cell activation by respiratory syncytial virus‐specific antibodies is decreased in infants with severe respiratory infections and correlates with Fc‐glycosylation

“…However, this can only be firmly concluded when general glycosylation patterns of RSV‐specific antibodies made by the infant are known. An alternative explanation for the age‐related changes in glycosylation of RSV‐specific antibodies is extracellular glycan modification of antibodies, but this remains speculative and has thus far only been shown for sialylation . Even for sialylation, most of the incorporated sialic acid is still expected to be assembled in the B cells, as antigen‐specific antibodies formed in certain immune responses can deviate markedly from total IgG …”