Basic and clinical immunology of Siglecs

Abstract

Siglecs are cell-surface proteins found primarily on hematopoietic cells. By definition, they are members of the immunoglobulin gene super-family and bind sialic acid. Most contain cytoplasmic tyrosine motifs implicated in cell signaling. This review will first summarize characteristics common and unique to Siglecs, followed by a discussion of each human Siglec in numerical order, mentioning in turn its closest murine ortholog or paralog. Each section will describe its pattern of cellular expression, latest known immune functions, ligands, and signaling pathways, with the focus being predominantly on CD33-related Siglecs. Potential clinical and therapeutic implications of each Siglec will also be covered.

Figure 1

Nomenclature and key structural characteristics of human Siglecs. Although 15 are shown, Siglec-13 is present in nonhuman primates but not in man. V structures indicate the arginine-containing V-set domains with lectin activity; these are followed by C2-type Ig repeat domains. U-shaped structures for Siglec-XII indicate the mutated V-set domains missing arginine that have lost their lectin activity. Also shown is DAP12, illustrated as a shorter transmembrane structure co-associating with Siglec-13, Siglec-14, and Siglec-15. See key for symbols representing cytoplasmic signaling motifs.

Figure 2

Nomenclature and key structural characteristics of mouse Siglecs. V structures indicate the arginine-containing V-set domains with lectin activity; these are followed by C2-type Ig repeat domains. Also shown is DAP12, illustrated as a shorter transmembrane structure co-associating with Siglec-15 and Siglec-H. Whether Siglec-H, shown as having an arginine-containing V-set domains with lectin activity, can bind sialic acid ligands remains controversial (see text). Note that Siglecs-1–4 are conserved with humans, as is Siglec-15 (compare to Fig. 1). While not true orthologs, the closest functional paralog of Siglec-E is Siglec-9, while Siglec-F resembles Siglec-8 and Siglec-G resembles Siglec-10.

Figure 3

Relative affinities of Siglecs with selected sialoside sequences. A comparison of the sialoside specificities, obtained from glycan array analysis and competitive binding experiments, for several sialic acid–binding immunoglobulin-like lectins (Siglecs) against selected sialoside sequences found in mammalian glycoproteins and glycolipids^,,, (see also the Functional Glycomics web site). Despite the general low affinity of Siglecs toward the common mammalian sialoside structures containing the N-acetylneuraminic acid (Neu5 Ac) α2–6 and α2–3 linkages, examination of the binding of each individual Siglec to a range of common sialoside structures shows that a unique sialoside specificity profile is characteristic of each Siglec. +++, strong binding; ++, moderate binding; +, low binding; ±, detectable binding; 0, no detectable binding; GlcNAc, N-acetylglucosamine; ND, not determined; Neu5 Gc, N-glycolylneuraminic acid. Legend and figure reproduced from Ref. with permission.