New I-type lectins of the CD 33-related siglec subgroup identified through genomics

2002 ◽  
Vol 69 ◽  
pp. 83-94 ◽  
Author(s):  
Paul R. Crocker ◽  
Jiquan Zhang
Keyword(s):  
Immune System ◽  
Sialic Acid ◽  
Immune Responses ◽  
Expression Patterns ◽  
Binding Properties ◽  
Immune Systems ◽  
Sialic Acid Binding ◽  
Ig Superfamily ◽  
Functional Screens ◽  
Signalling Motifs

Siglecs are sialic-acid-binding proteins of the Ig superfamily that are involved in cell–cell interactions and signalling. In recent years, several novel siglecs that are highly related to CD33/Siglec-2 have been identified through genomics and functional screens. In addition to their distinct sialic-acid-binding properties, most of these novel siglecs bear tyrosine-based signalling motifs that are typically found in inhibitory receptors of the immune system. The restricted expression patterns of CD33-related siglecs in the haemopoietic and immune systems suggests that they are involved in regulating leucocyte activation during inflammatory and immune responses.

Siglecs as positive and negative regulators of the immune system

2008 ◽  
Vol 36 (6) ◽  
pp. 1467-1471 ◽  
Author(s):  
Paul R. Crocker ◽  
Pierre Redelinghuys
Keyword(s):  
Immune System ◽  
Immune Responses ◽  
Rapid Evolution ◽  
Negative Regulators ◽  
Adaptive Immune Responses ◽  
Enveloped Viruses ◽  
Adaptive Immune ◽  
Sialic Acid Binding ◽  
Pattern Recognition Molecule ◽  
Recognition Molecule

Siglecs (sialic acid-binding Ig-like lectins) are mainly expressed in the immune system. Sn (sialoadhesin) (siglec-1), CD22 (siglec-2) and siglec-15 are well conserved, whereas the CD33-related siglecs are undergoing rapid evolution, as reflected in large differences in repertoires among the different mammals studied so far. In the present paper, we review recent findings on the signalling properties of the CD33-related siglecs and discuss the emergence of both inhibitory and activating forms of this family. We also discuss how Sn may function as a positive regulator of adaptive immune responses and its emerging role as an induced macrophage pattern-recognition molecule for sialylated pathogens, especially enveloped viruses.

Differential Expression and Function of the CD33-Related Siglecs between Humans and Great Apes.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1466-1466
Author(s):  
Nancy Hurtado-Ziola ◽  
Justin L. Sonnenburg ◽  
Ajit Varki
Keyword(s):  
Sialic Acid ◽  
Blood Cells ◽  
Expression Patterns ◽  
Great Apes ◽  
Sialic Acids ◽  
Innate Immune ◽  
Immunoglobulin Superfamily ◽  
Last Common Ancestor ◽  
Great Ape ◽  
Sialic Acid Binding

Abstract The Siglecs (Sialic acid-binding Immunoglobulin Superfamily Lectins) are a recently discovered family of mammalian glycan-binding proteins that have been shown to recognize the terminal sialic acids of glycoproteins and glycolipids. The CD33-Related Siglecs (CD33rSiglecs, namely Siglec-3, -5 through -11 and -XII in humans) are a subgroup of these molecules, which are thought to be primarily expressed on cells of the innate immune system. All CD33rSiglecs are type-1 transmembrane proteins with an N-terminal sialic acid-recognizing V-set domain followed by a variable number of C-2 set domains, a transmembrane region and a cytosolic C-terminal domain that usually has two tyrosine-based signaling motifs, one of which conforms to a canonical negative regulatory ITIM motif. Although the true function of the CD33rSiglecs has yet to be discovered, available data are most consistent with an inhibitory signaling role in the innate immune response, mediated by recognition of host sialic acids as “self”. CD33rSiglecs also interact with sialic acids on the same cell surface, typically resulting in “masking” of their sialic acid-binding sites. Our recent studies have shown that humans and non-human primates have a similar clustered localization of CD33rSiglec genes, and that true orthologs can generally be identified within each cluster (Angata et al., PNAS, in press). However, humans no longer express CMP-sialic acid hydroxylase (CMAH) the enzyme required to generate one of the potential CD33rSiglec sialic acid ligands called N-glycolylneuraminic acid (Neu5Gc), from its precursor N-acetylneuraminic acid (Neu5Ac). This genetic change occurred after our last common ancestor with the great apes, and dramatically altered the “Sialome” (the sialic acid makeup of a specific species) of humans when compared to that of the great apes. While great ape blood cells express about equal amounts of Neu5Ac and Neu5Gc, human blood cells express almost exclusively Neu5Ac. We also recently discovered that preferential recognition of Neu5Gc is the ancestral condition of most or all of the great ape (chimpanzee and gorilla) CD33rSiglecs (Sonnenburg JL, Altheide TK, Varki A. Glycobiology.14:339–46, 2004). We therefore reasoned that the sudden and major change in the sialome of our hominid ancestors could have had a significant impact on the evolution, binding specificities and expression patterns of CD33rSiglecs. Indeed, we have found that all human CD33rSiglecs can recognize both Neu5Ac and Neu5Gc. This presumably represents an evolutionarily-selected “relaxation” in binding specificity that was necessary to “remask” the Siglecs that had lost their Neu5Gc ligands. Also, there are differences in CD33rSiglec expression on monocytes and neutrophils between humans and great apes (chimp, bonobo, gorilla and orangutan). Furthermore, while great ape cells often show multiple populations with different signal intensities, humans express a single bright peak for each Siglec in flow cytometry. Surprisingly, while humans showed almost no CD33rSiglec expression on lymphocytes, the great apes show a moderate to high expression of some Siglecs on these cells. Total leukocyte expression of some CD33rSiglecs also shows differences between humans and great apes. Overall, CD33rSiglecs appear to be rapidly evolving in primates, with an apparent further acceleration of changes in humans. Additional studies are needed to define the mechanistic details, as well as the implications for human health and disease.

scholarly journals Characterization of Sialic Acid-Binding Immunoglobulin-Type Lectins in Fish Reveals Teleost-Specific Structures and Expression Patterns

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 836
Author(s):  
Kim F. Bornhöfft ◽  
Joan Martorell Ribera ◽  
Torsten Viergutz ◽  
Marzia T. Venuto ◽  
Ulrike Gimsa ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Sander Lucioperca ◽  
Handling Stress ◽  
Sialic Acid Binding ◽  
Specific Manner ◽  
Genes Encoding ◽  
Myelin Associated Glycoprotein

The cellular glycocalyx of vertebrates is frequently decorated with sialic acid residues. These sialylated structures are recognized by sialic acid-binding immunoglobulin-type lectins (Siglecs) of immune cells, which modulate their responsiveness. Fifteen Siglecs are known to be expressed in humans, but only four Siglecs are regularly present in fish: Siglec1, CD22, myelin-associated glycoprotein (MAG), and Siglec15. While several studies have dealt with the physiological roles of these four Siglecs in mammals, little is known about Siglecs in fish. In the present manuscript, the expression landscapes of these Siglecs were determined in the two salmonid species Oncorhynchus mykiss and Coregonus maraena and in the percid fish Sander lucioperca. This gene-expression profiling revealed that the expression of MAG is not restricted to neuronal cells but is detectable in all analyzed blood cells, including erythrocytes. The teleostean MAG contains the inhibitory motif ITIM; therefore, an additional immunomodulatory function of MAG is likely to be present in fish. Besides MAG, Siglec1, CD22, and Siglec15 were also expressed in all analyzed blood cell populations. Interestingly, the expression profiles of genes encoding Siglecs and particular associated enzymes changed in a gene- and tissue-specific manner when Coregonus maraena was exposed to handling stress. Thus, the obtained data indicate once more that stress directly affects immune-associated processes.

scholarly journals Siglec-7 Undergoes a Major Conformational Change When Complexed with the α(2,8)-Disialylganglioside GT1b

2006 ◽  
Vol 281 (43) ◽  
pp. 32774-32783 ◽  
Author(s):  
Helen Attrill ◽  
Akihiro Imamura ◽  
Ritu S. Sharma ◽  
Makoto Kiso ◽  
Paul R. Crocker ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Immune System ◽  
Sialic Acid ◽  
Binding Site ◽  
Structural Data ◽  
Site Structure ◽  
Sialic Acid Binding ◽  
Structural Template ◽  
Polar Interactions ◽  
Ganglioside Gt1b

The siglecs are a group of mammalian sialic acid binding receptors expressed predominantly in the immune system. The CD33-related siglecs show complex recognition patterns for sialylated glycans. Siglec-7 shows a preference for α(2,8)-disialylated ligands and provides a structural template for studying the key interactions that drive this selectivity. We have co-crystallized Siglec-7 with a synthetic oligosaccharide corresponding to the α(2,8)-disialylated ganglioside GT1b. The crystal structure of the complex offers a first glimpse into how this important family of lectins binds the structurally diverse gangliosides. The structure reveals that the C-C′ loop, a region implicated in previous studies as driving siglec specificity, undergoes a dramatic conformational shift, allowing it to interact with the underlying neutral glycan core of the ganglioside. The structural data in combination with mutagenesis studies show that binding of the ganglioside is driven by extensive hydrophobic contacts together with key polar interactions and that the binding site structure is complementary to preferred solution conformations of GT1b.

scholarly journals Cloning and Characterization of Siglec-10, a Novel Sialic Acid Binding Member of the Ig Superfamily, from Human Dendritic Cells

2001 ◽  
Vol 276 (30) ◽  
pp. 28106-28112 ◽  
Author(s):  
Nan Li ◽  
Weiping Zhang ◽  
Tao Wan ◽  
Jia Zhang ◽  
Taoyong Chen ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Sialic Acid ◽  
Sialic Acid Binding ◽  
Ig Superfamily ◽  
Human Dendritic Cells

scholarly journals Siglec Ligands

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1260
Author(s):  
Anabel Gonzalez-Gil ◽  
Ronald L. Schnaar
Keyword(s):  
Immune System ◽  
Sialic Acid ◽  
Therapeutic Intervention ◽  
Binding Proteins ◽  
Cellular Responses ◽  
Cell Physiology ◽  
Molecular Pathways ◽  
Cell Surfaces ◽  
Sugar Moiety ◽  
Sialic Acid Binding

A dense and diverse array of glycans on glycoproteins and glycolipids decorate all cell surfaces. In vertebrates, many of these carry sialic acid, in a variety of linkages and glycan contexts, as their outermost sugar moiety. Among their functions, glycans engage complementary glycan binding proteins (lectins) to regulate cell physiology. Among the glycan binding proteins are the Siglecs, sialic acid binding immunoglobulin-like lectins. In humans, there are 14 Siglecs, most of which are expressed on overlapping subsets of immune system cells. Each Siglec engages distinct, endogenous sialylated glycans that initiate signaling programs and regulate cellular responses. Here, we explore the emerging science of Siglec ligands, including endogenous sialoglycoproteins and glycolipids and synthetic sialomimetics. Knowledge in this field promises to reveal new molecular pathways controlling cell physiology and new opportunities for therapeutic intervention.

Immune system physiology in anaesthetic practice

2017 ◽  
Author(s):  
Helen F. Galley ◽  
Heather M. Wilson
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Immune Responses ◽  
Adaptive Immune Response ◽  
Innate Immune ◽  
Immune Systems ◽  
Adaptive Immune ◽  
System Physiology ◽  
Adaptive Immune Systems ◽  
Immune System Physiology

The immune system provides protection against invading pathogens, foreign cells including tumour cells, and macromolecules. It comprises an early, non-specific, innate immune response and a later, specific, adaptive immune response that helps prevent disease or recurrence of disease. Innate and adaptive immune systems work together with mutual interactivity distinguishing ‘self’ from ‘non-self components’ to provide effective immune responses and prevent infection. This chapter describes the basic processes involved in immune responses and illustrates the particular relevance for some disease processes as well as highlighting stresses associated with anaesthesia and surgery that can modulate responses.

Siglecs as Immune Cell Checkpoints in Disease

2020 ◽  
Vol 38 (1) ◽  
pp. 365-395 ◽  
Author(s):  
Shiteng Duan ◽  
James C. Paulson
Keyword(s):  
Immune System ◽  
Sialic Acid ◽  
Cell Signaling ◽  
Blood Cells ◽  
Immune Cell ◽  
White Blood Cells ◽  
Therapeutic Interventions ◽  
Cell Type ◽  
Cell Responses ◽  
Sialic Acid Binding

Sialic acid–binding immunoglobulin-type lectins (Siglecs) are expressed on the majority of white blood cells of the immune system and play critical roles in immune cell signaling. Through recognition of sialic acid–containing glycans as ligands, they help the immune system distinguish between self and nonself. Because of their restricted cell type expression and roles as checkpoints in immune cell responses in human diseases such as cancer, asthma, allergy, neurodegeneration, and autoimmune diseases they have gained attention as targets for therapeutic interventions. In this review we describe the Siglec family, its roles in regulation of immune cell signaling, current efforts to define its roles in disease processes, and approaches to target Siglecs for treatment of human disease.

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