Possible Influences of Endogenous and Exogenous Ligands on the Evolution of Human Siglecs

Sialic acids, a group of acidic sugars abundantly expressed in the tissues of deuterostome animals but rarely found in microbes, serve as a “signature of self” for these animals. Cognate sensors for sialic acids include Siglecs, a family of transmembrane lectins of vertebrate immune systems that recognize glycans containing sialic acids. A type of sialic acid called N-glycolylneuraminic acid (Neu5Gc) is abundant in many mammalian lineages including great apes, the closest extant relatives of modern human, but was lost in the lineage leading to modern human via the pseudogenization of the CMAH gene encoding the enzyme that converts N-acetylneuraminic acid (Neu5Ac) to Neu5Gc. Loss of Neu5Gc appears to have influenced the evolution of human Siglecs, such as the adjustment of sialic acid binding preferences and the inactivation of at least one Siglec. In addition, various mechanistic studies using model systems and genetic association studies have revealed that some human Siglecs interact with pathogens and influence the outcome of infections, and these pathogens in turn likely influence the evolution of these Siglecs. By understanding the evolutionary forces affecting Siglecs, we shall achieve a better appreciation of Siglec functions, and by understanding Siglec functions, we can obtain deeper insight into the evolutionary processes driving Siglec evolution

Siglec-5 and Siglec-14 are polymorphic paired receptors that modulate neutrophil and amnion signaling responses to group B Streptococcus

Group B Streptococcus (GBS) causes invasive infections in human newborns. We recently showed that the GBS beta-protein attenuates innate immune responses by binding to sialic acid-binding immunoglobulin-like lectin 5 (Siglec-5), an inhibitory receptor on phagocytes. Interestingly, neutrophils and monocytes also express Siglec-14, which has a ligand-binding domain almost identical to Siglec-5 but signals via an activating motif, raising the possibility that these are paired Siglec receptors that balance immune responses to pathogens. Here we show that beta-protein-expressing GBS binds to both Siglec-5 and Siglec-14 on neutrophils and that the latter engagement counteracts pathogen-induced host immune suppression by activating p38 mitogen-activated protein kinase (MAPK) and AKT signaling pathways. Siglec-14 is absent from some humans because of a SIGLEC14-null polymorphism, and homozygous SIGLEC14-null neutrophils are more susceptible to GBS immune subversion. Finally, we report an unexpected human-specific expression of Siglec-5 and Siglec-14 on amniotic epithelium, the site of initial contact of invading GBS with the fetus. GBS amnion immune activation was likewise influenced by the SIGLEC14-null polymorphism. We provide initial evidence that the polymorphism could influence the risk of prematurity among human fetuses of mothers colonized with GBS. This first functionally proven example of a paired receptor system in the Siglec family has multiple implications for regulation of host immunity

I-Type Lectins

I-type lectins are defined as glycan-binding proteins (excluding antibodies and T-cell receptors) in which the binding domain is homologous to the large and varied immunoglobulin superfamily (IgSF) of proteins. Among I-type lectins, the Siglec family of sialic acid–recognizing lectins is the best characterized subgroup, both structurally and functionally, and is therefore the major focus of this chapter. Details of their discovery, characterization, binding properties, and biology are provided, along with discussions of their functional roles in vertebrate biology, with most currently available information being in mammals, and multiple unusual changes during human evolution

Handbook of Glycosyltransferases and Related Genes

XXXVIII, 1707 p. 205 illus., 75 illus. in color.

Defining the in vivo function of Siglec-F, a CD33-related Siglec expressed on mouse eosinophils

CD33-related Siglecs (CD33rSiglecs) are a family of sialic acid–recognizing lectins on immune cells whose biologic functions are unknown. We studied in vivo functions of Siglec-F, the CD33rSiglec expressed on mouse eosinophils, which are prominent in allergic processes. Induction of allergic lung inflammation in mice caused up-regulation of Siglec-F on blood and bone marrow eosinophils, accompanied by newly induced expression on some CD4+ cells, as well as quantitative up-regulation of endogenous Siglec-F ligands in the lung tissue and airways. Taken together with the tyrosine-based inhibitory motif in the cytosolic tail of Siglec-F, the data suggested a negative feedback loop, controlling allergic responses of eosinophils and helper T cells, via Siglec-F and Siglec-F ligands. To pursue this hypothesis, we created Siglec-F–null mice. Allergen-challenged null mice showed increased lung eosinophil infiltration, enhanced bone marrow and blood eosinophilia, delayed resolution of lung eosinophilia, and reduced peribronchial-cell apoptosis. Anti–Siglec-F antibody cross-linking also enhanced eosinophil apoptosis in vitro. These data support the proposed negative feedback role for Siglec-F, represent the first in vivo demonstration of biologic functions for any CD33rSiglec, and predict a role for human Siglec-8 (the isofunctional paralog of mouse Siglec-F) in regulating the pathogenesis of human eosinophil-mediated disorders