Siglecs as modulators of macrophage phenotype and function.

The sialic acid-binding immunoglobulin-like lectins (Siglecs) are a family of receptors expressed widely on cells of the hematopoietic system. Siglecs recognize terminal sialic acid residues on glycans and often initiate intracellular signaling upon ligation. Cells can express several Siglec family members concurrently with each showing differential specificities for sialic acid linkages to the underlying glycan as well as varied hydroxyl substitutions, allowing these receptors to fine tune downstream responses.

IgG sialylation occurs via the FcRn-mediated recycling pathway in endothelial cells.

IgG is a key mediator of immune responses throughout the human body, and the structure of the conserved glycan on the Fc region has been identified as a key inflammatory switch regulating its downstream effects. In particular, the absence of terminal sialic acid has been shown to increase the affinity of IgG for activating Fc receptors, cascading the inflammatory response in a variety of diseases and conditions. Previously, we have shown that IgG sialylation is mediated by B cell-extrinsic processes.

Platelet-localized ST6Gal1 does not impact IgG sialylation.

The IgG antibody class forms an important basis of the humoral immune response, conferring reciprocal protection from both pathogens and autoimmunity. IgG function is determined by the IgG subclass, as defined by the heavy chain, as well as the glycan composition at N297, the conserved site of N-glycosylation within the Fc domain. For example, lack of core fucose promotes increased antibody-dependent cellular cytotoxicity, whereas α2,6-linked sialylation by the enzyme ST6Gal1 helps to drive immune quiescence.