Editorial: Carbohydrates: The Yet to be Tasted Sweet Spot of Immunity.

Abstract

Glycobiology is an expanding discipline. Nowhere is this more apparent than in our understanding of the immune response. Perhaps the title of this focused research topic should be: “Carbohydrates: now the sweet spot of immunity!” The revolution in thinking to embrace the “glyco” component of glycoproteins and glycolipids has been accompanied by the development of new technologies that allow the structure of many different glycans to be determined. The article by van Kooyk et al. provides an introduction to glycan analytical tools (1). These range from technically simple analyses using plant lectins combined with flow cytometry or ELISA methods to obtain clues of glycan structures, to more complex sequencing methodologies for detailed structural characterizations. Nevertheless, determining the structure of some glycans, and particularly the glycosaminoglycans (GAGs), is still extremely difficult. However, good progress is beingmade in this area (2). Cell surface glycosylation is a characteristic of all living cells (3, 4), thus it is logical that glycan structures are involved in self or non-self recognition. Nevertheless, glycans have been excluded from the thinking of most immunologists. Probably a lack of appreciation of the specificity of carbohydrate–protein interactions and the diversity of glycan structures led to this outcome. Yet, it is glycan diversity that has been harnessed bymicrobes to coat their surfaces, andmost immunogens onmicrobes are glycans. As pathogens developed their glycan coats their vertebrate and invertebrate hosts similarly developed molecules to recognize these structures. The idea that invertebrate lectins can recognize glycan structures onmicrobes, thereby facilitatingmicrobe phagocytosis, was accepted decades ago (5), but the fundamental contribution of glycan–protein interactions to mammalian immunity was accepted only recently. Numerous molecules involved in invertebrate host defense that recognize a spectrum of glycan structures on bacteria, fungi, and other pathogens are clearly related to similarly acting proteins in modern mammals (6). The lectin pathway of complement, toll-like receptors, the pentraxin pattern recognition receptors, and the galectins all probably arose initially in invertebrates ancestors and had roles in self or non-self recognition.Wenowknowglycans and their binding proteins contribute to all aspects of immunology. It was argued that the essential role glycan–protein binding events play in host defense and infection is the driver of glycan diversity (3, 4). The evolutionary selection pressures imposed by the need of pathogens to avoid recognition by the proteins of their host’s immune system, and for hosts to rapidly evolve glycan structures that are not sites for pathogen adhesion and infection, it was proposed, led to the conservation of glycan structural diversity (3, 4). An appreciation of carbohydrate structural diversity is obtained when the number of genes involved in glycan biosynthesis is appreciated. van Kooyk et al. revealed that if all the genes involved in glycan biosynthesis are considered they would comprise around 3–4% of the genome (1). Although they primarily encode enzymes, co-factors, transporters, and activated sugar donors are also involved. Regulation of the expression of these genes, regulation of the activity of the different glycosyltransferases through a diverse collection of mechanisms, coupled with regulation of the expression of core proteins adds an extra dimension to glycoconjugate structural diversity (1).